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1. An atlas of healthy and injured cell states and niches in the human kidney.

Author

Lake, Blue, Menon, Rajasree, Winfree, Seth, Hu, Qiwen, Ferreira, Ricardo, Kalhor, Kian, Barwinska, Daria, Otto, Edgar, Ferkowicz, Michael, Diep, Dinh, Plongthongkum, Nongluk, Knoten, Amanda, Urata, Sarah, Mariani, Laura, Naik, Abhijit, Eddy, Sean, Zhang, Bo, Wu, Yan, Salamon, Diane, Williams, James, Wang, Xin, Balderrama, Karol, Hoover, Paul, Murray, Evan, Marshall, Jamie, Noel, Teia, Vijayan, Anitha, Hartman, Austin, Chen, Fei, Waikar, Sushrut, Rosas, Sylvia, Wilson, Francis, Palevsky, Paul, Kiryluk, Krzysztof, Sedor, John, Toto, Robert, Parikh, Chirag, Kim, Eric, Satija, Rahul, Greka, Anna, Macosko, Evan, Kharchenko, Peter, Gaut, Joseph, Hodgin, Jeffrey, Eadon, Michael, Dagher, Pierre, El-Achkar, Tarek, Kretzler, Matthias, Jain, Sanjay, and Zhang, Kun

Subjects
Humans, Cell Nucleus, Gene Expression Profiling, Kidney, Kidney Diseases, Transcriptome, Single-Cell Analysis, Case-Control Studies, Imaging, Three-Dimensional
Abstract

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Published
2023

2. Protective role for kidney TREM2high macrophages in obesity- and diabetes-induced kidney injury

Author

Ayshwarya Subramanian, Katherine A. Vernon, Yiming Zhou, Jamie L. Marshall, Maria Alimova, Carlos Arevalo, Fan Zhang, Michal Slyper, Julia Waldman, Monica S. Montesinos, Danielle Dionne, Lan T. Nguyen, Michael S. Cuoco, Dan Dubinsky, Jason Purnell, Keith Keller, Samuel H. Sturner, Elizabeth Grinkevich, Ayan Ghoshal, Amanda Kotek, Giorgio Trivioli, Nathan Richoz, Mary B. Humphrey, Isabella G. Darby, Sarah J. Miller, Yingping Xu, Astrid Weins, Alexandra Chloe-Villani, Steven L. Chang, Matthias Kretzler, Orit Rosenblatt-Rosen, Jillian L. Shaw, Kurt A. Zimmerman, Menna R. Clatworthy, Aviv Regev, and Anna Greka

Subjects
CP: Immunology, Biology (General), QH301-705.5
Abstract

Summary: Diabetic kidney disease (DKD), the most common cause of kidney failure, is a frequent complication of diabetes and obesity, and yet to date, treatments to halt its progression are lacking. We analyze kidney single-cell transcriptomic profiles from DKD patients and two DKD mouse models at multiple time points along disease progression—high-fat diet (HFD)-fed mice aged to 90–100 weeks and BTBR ob/ob mice (a genetic model)—and report an expanding population of macrophages with high expression of triggering receptor expressed on myeloid cells 2 (TREM2) in HFD-fed mice. TREM2high macrophages are enriched in obese and diabetic patients, in contrast to hypertensive patients or healthy controls in an independent validation cohort. Trem2 knockout mice on an HFD have worsening kidney filter damage and increased tubular epithelial cell injury, all signs of worsening DKD. Together, our studies suggest that strategies to enhance kidney TREM2high macrophages may provide therapeutic benefits for DKD.

Published
2024
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3. Protective role for kidney TREM2high macrophages in obesity- and diabetes-induced kidney injury

Author

Subramanian, Ayshwarya, Vernon, Katherine A., Zhou, Yiming, Marshall, Jamie L., Alimova, Maria, Arevalo, Carlos, Zhang, Fan, Slyper, Michal, Waldman, Julia, Montesinos, Monica S., Dionne, Danielle, Nguyen, Lan T., Cuoco, Michael S., Dubinsky, Dan, Purnell, Jason, Keller, Keith, Sturner, Samuel H., Grinkevich, Elizabeth, Ghoshal, Ayan, Kotek, Amanda, Trivioli, Giorgio, Richoz, Nathan, Humphrey, Mary B., Darby, Isabella G., Miller, Sarah J., Xu, Yingping, Weins, Astrid, Chloe-Villani, Alexandra, Chang, Steven L., Kretzler, Matthias, Rosenblatt-Rosen, Orit, Shaw, Jillian L., Zimmerman, Kurt A., Clatworthy, Menna R., Regev, Aviv, and Greka, Anna

Published
2024
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4. Precision Medicine in Nephrology: An Integrative Framework of Multidimensional Data in the Kidney Precision Medicine Project

Author

Lake, Blue, Zhang, Kun, Lecker, Stewart, Morales, Alexander, Bogen, Steve, Amodu, Afolarin A., Beck, Laurence, Henderson, Joel, Ilori, Titlayo, Maikhor, Shana, Onul, Ingrid, Schmidt, Insa, Verma, Ashish, Waikar, Sushrut, Yadati, Pranav, Yu, Guanghao, Colona, Mia R., McMahon, Gearoid, Hacohen, Nir, Greka, Anna, Hoover, Paul J., Marshall, Jamie L., Aulisio, Mark, Bush, William, Chen, Yijiang, Crawford, Dana, Madabhushi, Anant, Viswanathan, Vidya S., Bush, Lakeshia, Cooperman, Leslie, Gadegbeku, Crystal, Herlitz, Leal, Jolly, Stacey, Nguyen, Jane, O’Malley, Charles, O’Toole, John, Palmer, Ellen, Poggio, Emilio, Spates-Harden, Kassandra, Sedor, John, Sendrey, Dianna, Taliercio, Jonathan, Appelbaum, Paul, Balderes, Olivia, Barasch, Jonathan, Berroue, Cecilia, Bomback, Andrew, Canetta, Pietro A., D’Agati, Vivette, Kiryluk, Krzysztof, Kudose, Satoru, Mehl, Karla, Sabatello, Maya, Shang, Ning, de Pinho Gonçalves, Joana, Lardenoije, Roy, Migas, Lukasz, Van de Plas, Raf, Rennke, Helmut, Azeloglu, Evren, Campbell, Kirk, Coca, Steven, He, Cijang, He, John, Iyengar, Srinivas Ravi, Lefferts, Seanee, Nadkarni, Girish, Patel, Marissa, Tokita, Joji, Ward, Stephen, Xiong, Yuguang, Verdoes, Abraham, Sabo, Angela, Barwinska, Daria, Gisch, Debora Lidia, Williams, James, Kelly, Katherine, Dunn, Kenneth, Asghari, Mahla, Eadon, Michael, Ferkowicz, Michael, Dagher, Pierre, Ferreira, Ricardo Melo, Winfree, Seth, Bledsoe, Sharon, Wofford, Stephanie, El-Achkar, Tarek, Sutton, Timothy, Bowen, William, Cheng, Ying-Hua, Slade, Austen, Record, Elizabeth, Cheng, Yinghua, Borner, Katy, Herr, Bruce, Jain, Yashvardhan, Quardokus, Ellen, Atta, Mohamed, Bernard, Lauren, Menez, Steven, Parikh, Chirag, Corona Villalobos, Celia Pamela, Wang, Ashley, Wen, Yumeng, Xu, Alan, Chen, Sarah, Donohoe, Isabel, Johansen, Camille, Rosas, Sylvia, Sun, Jennifer, Ardayfio, Joseph, Bebiak, Jack, Campbell, Taneisha, Fox, Monica, Knight, Richard, Koewler, Robert, Pinkeney, Roy, Saul, John, Shpigel, Anna, Prasad, Pottumarthi, Madhavan, Sethu M., Parikh, Samir, Rovin, Brad, Shapiro, John P., Anderton, Christopher, Lukowski, Jessica, Pasa-Tolic, Ljiljana, Velickovic, Dusan, Oliver, George, Mao, Weiguang, Sealfon, Rachel, Troyanskaya, Olga, Pollack, Ari, Goltsev, Yury, Ginley, Brandon, Anjani, Kavya, Laszik, Zoltan G., Mukatash, Tariq, Nolan, Garry, Beyda, David, Bracamonte, Erika, Brosius, Frank, Campos, Baltazar, Marquez, Nicole, Mendoza, Katherine, Scott, Raymond, Thajudeen, Bijin, Tsosie, Rebecca, Woodhead, Gregory, Saunders, Milda, Alloway, Rita R., Lee, Paul J., Rike, Adele, Shi, Tiffany, Woodle, E. Steve, Bjornstad, Petter, Hsieh, Elena, Kendrick, Jessica, Pyle, Laura, Thurman, Joshua, Vinovskis, Carissa, Wrobel, Julia, Lucarelli, Nicholas, Sarder, Pinaki, Bui, James, Carmona-Powell; Ron Gaba, Eunice, Kelly, Tanika, Lash, James, Meza, Natalie, Redmond, Devona, Renteria, Amada, Ricardo, Ana, Setty, Suman, Srivastava, Anand, Alakwaa, Fadhl, Ascani, Heather, Balis, Ul, Bitzer, Markus, Blanc, Victoria, Bonevich, Nikki, Conser, Ninive, Demeke, Dawit, Dull, Rachel, Eddy, Sean, Frey, Renee, Hartman, John, He, Yongqun Oliver, Hodgin, Jeffrey, Kretzler, Matthias, Lienczewski, Chrysta, Luo, Jinghui, Mariani, Laura, McCown, Phillip, Menon, Rajasree, Nair, Viji, Otto, Edgar, Reamy, Rebecca, Rose, Michael, Schaub, Jennifer, Steck, Becky, Wright, Zachary, Coleman, Alyson, Henderson-Brown; Jerica Berge, Dorisann, Caramori, Maria Luiza, Adeyi, Oyedele, Nachman, Patrick, Safadi, Sami, Flanagan, Siobhan, Ma, Sisi, Klett, Susan, Wolf, Susan, Harindhanavudhi, Tasma, Rao, Via, Bream, Peter, Froment, Anne, Kelley, Sara, Mottl, Amy, Chaudhury; Evan Zeitler, Prabir Roy, Bender, Filitsa, Elder, Michele, Gilliam, Matthew, Hall, Daniel E., Kellum, John A., Murugan, Raghavan, Palevsky, Paul, Rosengart, Matthew, Tan, Roderick, Tublin, Mitchell, Winters, James, Bansal, Shweta, Montellano, Richard, Pamreddy, Annapurna, Sharma, Kumar, Venkatachalam, Manjeri, Ye, Hongping, Zhang, Guanshi, Basit, Mujeeb, Cai, Qi, Hendricks, Allen, Hedayati, Susan, Kermani, Asra, Lee, Simon C., Ma, Shihong, Miller, Richard Tyler, Moe, Orson W., Park, Harold, Patel, Jiten, Pillai, Anil, Sambandam, Kamalanathan, Torrealba, Jose, Toto, Robert D., Vazquez, Miguel, Wang, Nancy, Wen, Natasha, Zhang, Dianbo, Alpers, Charles, Berglund, Ashley, Berry, Brooke, Blank, Kristina, Brown, Keith, Carson, Jonas, Daniel, Stephen, de Boer, Ian H., Dighe, Ashveena L., Dowd, Frederick, Grewenow, Stephanie M., Himmelfarb, Jonathan, Hoofnagle, Andrew, Jefferson, Nichole, Larson, Brandon, Limonte, Christine, McClelland, Robyn, Mooney, Sean, Nam, Yunbi, Park, Christopher, Phuong, Jimmy, Rezaei, Kasra, Roberts, Glenda, Sarkisova, Natalya, Shankland, Stuart, Snyder, Jaime, Stutzke, Christy, Tuttle, Katherine, Wangperawong, Artit, Wilcox, Adam, Williams, Kayleen, Young, Bessie, Allen, Jamie, Caprioli, Richard M., de Caestecker, Mark, Djambazova, Katerina, Dufresne, Martin, Farrow, Melissa, Fogo, Agnes, Sharman, Kavya, Spraggins, Jeffrey, Basta, Jeannine, Conlon, Kristine, Diettman, Sabine M., Gaut, Joseph, Kaushal, Madhurima, Jain, Sanjay, Knoten, Amanda, Minor, Brittany, Nwanne, Gerald, Vijayan, Anitha, Zhang, Bo, Arora, Tanima, Cantley, Lloyd, Victoria Castro, Angela M., Kakade, Vijayakumar, Moeckel, Gilbert, Moledina, Dennis, Shaw, Melissa, Wilson, Francis P., El-Achkar, Tarek M., and Eadon, Michael T.

Published
2024
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5. N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model

Author

Suzzi, Stefano, Croese, Tommaso, Ravid, Adi, Gold, Or, Clark, Abbe R., Medina, Sedi, Kitsberg, Daniel, Adam, Miriam, Vernon, Katherine A., Kohnert, Eva, Shapira, Inbar, Malitsky, Sergey, Itkin, Maxim, Brandis, Alexander, Mehlman, Tevie, Salame, Tomer M., Colaiuta, Sarah P., Cahalon, Liora, Slyper, Michal, Greka, Anna, Habib, Naomi, and Schwartz, Michal

Published
2023
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6. SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity

Author

Carrasquillo Robert, Tian Dequan, Krishna Sneha, Pollak Martin R, Greka Anna, and Schlöndorff Johannes

Subjects
Transient receptor potential, Calcium channel, Protein-protein interaction, Calcineurin-NFAT signaling, Cytology, QH573-671
Abstract

Abstract Background Transient receptor potential canonical (TRPC) channels are non-selective cation channels involved in receptor-mediated calcium signaling in diverse cells and tissues. The canonical transient receptor potential 6 (TRPC6) has been implicated in several pathological processes, including focal segmental glomerulosclerosis (FSGS), cardiac hypertrophy, and pulmonary hypertension. The two large cytoplasmic segments of the cation channel play a critical role in the proper regulation of channel activity, and are involved in several protein-protein interactions. Results Here we report that SNF8, a component of the endosomal sorting complex for transport-II (ESCRT-II) complex, interacts with TRPC6. The interaction was initially observed in a yeast two-hybrid screen using the amino-terminal cytoplasmic domain of TRPC6 as bait, and confirmed by co-immunoprecipitation from eukaryotic cell extracts. The amino-terminal 107 amino acids are necessary and sufficient for the interaction. Overexpression of SNF8 enhances both wild-type and gain-of-function mutant TRPC6-mediated whole-cell currents in HEK293T cells. Furthermore, activation of NFAT-mediated transcription by gain-of-function mutants is enhanced by overexpression of SNF8, and partially inhibited by RNAi mediated knockdown of SNF8. Although the ESCRT-II complex functions in the endocytosis and lysosomal degradation of transmembrane proteins, SNF8 overexpression does not alter the amount of TRPC6 present on the cell surface. Conclusion SNF8 is novel binding partner of TRPC6, binding to the amino-terminal cytoplasmic domain of the channel. Modulating SNF8 expression levels alters the TRPC6 channel current and can modulate activation of NFAT-mediated transcription downstream of gain-of-function mutant TRPC6. Taken together, these results identify SNF8 as a novel regulator of TRPC6.

Published
2012
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7. Gasdermin D pore structure reveals preferential release of mature interleukin-1

Author

Xia, Shiyu, Zhang, Zhibin, Magupalli, Venkat Giri, Pablo, Juan Lorenzo, Dong, Ying, Vora, Setu M, Wang, Longfei, Fu, Tian-Min, Jacobson, Matthew P, Greka, Anna, Lieberman, Judy, Ruan, Jianbin, and Wu, Hao

Subjects
Biochemistry and Cell Biology, Biological Sciences, Generic health relevance, Animals, Caspase 1, Cryoelectron Microscopy, Humans, Inflammasomes, Interleukin-1, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Macrophages, Mice, Inbred C57BL, Phosphate-Binding Proteins, Protein Precursors, Protein Structure, Quaternary, Static Electricity, General Science & Technology
Abstract

As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis1-9. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-110. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.

Published
2021

8. Molecular Signatures of Glomerular Neovascularization in a Patient with Diabetic Kidney Disease

Author

Ferkowicz, Michael J., Verma, Ashish, Barwinska, Daria, Melo Ferreira, Ricardo, Henderson, Joel M., Kirkpatrick, Mary, Silva, Paolo S., Steenkamp, Devin W., Phillips, Carrie L., Waikar, Sushrut S., Sutton, Timothy A., Lake, Blue, Zhang, Kun, Lecker, Stewart, Morales, Alexander, Stillman, Isaac, Bogen, Steve, Amodu, Afolarin A., Beck, Laurence, Henderson, Joel, Ilori, Titlayo, Maikhor, Shana, Onul, Ingrid, Schmidt, Insa, Verma, Ashish, Waikar, Sushrut, Yadati, Pranav, Yu, Guanghao, Colona, Mia R., McMahon, Gearoid, Weins, Astrid, Hacohen, Nir, Greka, Anna, Hoover, Paul J., Marshall, Jamie L., Aulisio, Mark, Bush, William, Chen, Yijiang, Crawford, Dana, Madabhushi, Anant, Viswanathan, Vidya S., Bush, Lakeshia, Cooperman, Leslie, Gadegbeku, Crystal, Herlitz, Leal, Jolly, Stacey, Nguyen, Jane, O’Malley, Charles, O’Toole, John, Palmer, Ellen, Poggio, Emilio, Spates-Harden, Kassandra, Sedor, John, Sendrey, Dianna, Taliercio, Jonathan, Appelbaum, Paul, Balderes, Olivia, Barasch, Jonathan, Berroue, Cecilia, Bomback, Andrew, Canetta, Pietro A., D’Agati, Vivette, Kiryluk, Krzysztof, Kudose, Satoru, Mehl, Karla, Sabatello, Maya, Shang, Ning, Varela, German, de Pinho Gonçalves, Joana, Lardenoije, Roy, Migas, Lukasz, Van de Plas, Raf, Barisoni, Laura, Rennke, Helmut, Azeloglu, Evren, Campbell, Kirk, Coca, Steven, He, Cijang, He, John, Iyengar, Srinivas Ravi, Lefferts, Seanee, Nadkarni, Girish, Patel, Marissa, Tokita, Joji, Ward, Stephen, Xiong, Yuguang, Verdoes, Abraham, Sabo, Angela, Barwinska, Daria, Gisch, Debora Lidia, Williams, James, Kelly, Katherine, Dunn, Kenneth, Asghari, Mahla, Eadon, Michael, Ferkowicz, Michael, Dagher, Pierre, Ferreira, Ricardo Melo, Winfree, Seth, Bledsoe, Sharon, Wofford, Stephanie, El-Achkar, Tarek, Sutton, Timothy, Bowen, William, Cheng, Ying-Hua, Slade, Austen, Record, Elizabeth, Cheng, Yinghua, Borner, Katy, Herr, Bruce, Jain, Yashvardhan, Quardokus, Ellen, Atta, Mohamed, Bernard, Lauren, Menez, Steven, Parikh, Chirag, Corona Villalobos, Celia Pamela, Wang, Ashley, Wen, Yumeng, Xu, Alan, Chen, Sarah, Donohoe, Isabel, Johansen, Camille, Rosas, Sylvia, Sun, Jennifer, Ardayfio, Joseph, Bebiak, Jack, Brown, Keith, Campbell, Taneisha, Fox, Monica, Hayashi, Lynda, Jefferson, Nichole, Richard Knight, Jennifer Jones, Koewler, Robert, Pinkeney, Roy, Saul, John, Shpigel, Anna, Stutzke, Christy, Prasad, Pottumarthi, Madhavan, Sethu M., Parikh, Samir, Rovin, Brad, Shapiro, John P., Anderton, Christopher, Lukowski, Jessica, Pasa-Tolic, Ljiljana, Velickovic, Dusan, Oliver, George, Mao, Weiguang, Sealfon, Rachel, Troyanskaya, Olga, Wong, Aaron, Pollack, Ari, Goltsev, Yury, Ginley, Brandon, Lutnick, Brendon, Anjani, Kavya, Laszik, Zoltan G., Mukatash, Tariq, Nolan, Garry, Beyda, David, Bracamonte, Erika, Brosius, Frank, Campos, Baltazar, Marquez, Nicole, Mendoza, Katherine, Scott, Raymond, Thajudeen, Bijin, Tsosie, Rebecca, Woodhead, Gregory, Saunders, Milda, Alloway, Rita R., Lee, Paul J., Rike, Adele, Shi, Tiffany, Woodle, E. Steve, Bjornstad, Petter, Hsieh, Elena, Kendrick, Jessica, Pyle, Laura, Thurman, Joshua, Vinovskis, Carissa, Wrobel, Julia, Lucarelli, Nicholas, Sarder, Pinaki, Bui, James, Carmona-Powell, Eunice, Gaba, Ron, Kelly, Tanika, Lash, James, Meza, Natalie, Redmond, Devona, Renteria, Amada, Ricardo, Ana, Setty, Suman, Srivastava, Anand, Alakwaa, Fadhl, Ascani, Heather, Balis, Ul, Bitzer, Markus, Blanc, Victoria, Bonevich, Nikki, Conser, Ninive, Demeke, Dawit, Dull, Rachel, Eddy, Sean, Frey, Renee, Hartman, John, He, Yongqun Oliver, Hodgin, Jeffrey, Kretzler, Matthias, Lienczewski, Chrysta, Luo, Jinghui, Mariani, Laura, McCown, Phillip, Menon, Rajasree, Nair, Viji, Otto, Edgar, Reamy, Rebecca, Rose, Michael, Schaub, Jennifer, Steck, Becky, Wright, Zachary, Coleman, Alyson, Henderson-Brown, Dorisann, Berge, Jerica, Caramori, Maria Luiza, Adeyi, Oyedele, Nachman, Patrick, Safadi, Sami, Flanagan, Siobhan, Ma, Sisi, Klett, Susan, Wolf, Susan, Harindhanavudhi, Tasma, Rao, Via, Bream, Peter, Froment, Anne, Kelley, Sara, Mottl, Amy, Roy-Chaudhury, Prabir, Zeitler, Evan, Bender, Filitsa, Elder, Michele, Gilliam, Matthew, Hall, Daniel E., Kellum, John A., Murugan, Raghavan, Palevsky, Paul, Rosengart, Matthew, Tan, Roderick, Tublin, Mitchell, Winters, James, Bansal, Shweta, Montellano, Richard, Pamreddy, Annapurna, Sharma, Kumar, Venkatachalam, Manjeri, Ye, Hongping, Zhang, Guanshi, Basit, Mujeeb, Cai, Qi, Hendricks, Allen, Hedayati, Susan, and Asra

Published
2024
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9. Participant Experience with Protocol Research Kidney Biopsies in the Kidney Precision Medicine Project

Author

Victoria-Castro, Angela M., Corona-Villalobos, Celia P., Xu, Alan Y., Onul, Ingrid, Huynh, Courtney, Chen, Sarah W., Ugwuowo, Ugochukwu, Sarkisova, Natalya, Dighe, Ashveena L., Blank, Kristina N., Blanc, Victoria M., Rose, Michael P., Himmelfarb, Jonathan, de Boer, Ian H., Tuttle, Katherine R., Roberts, Glenda V., Alexandrov, Theodore, Alloway, Rita R., Alpers, Charles E., Amodu, Afolarin A., Anderton, Christopher R., Anjani, Kavya, Appelbaum, Paul, Ardayfio, Joseph, Arora, Tanima, Ascani, Heather, El-Achkar, Tarek M., Aulisio, Mark, Azeloglu, Evren U., Balderes, Olivia, Balis, Ulysses G.J., Bansal, Shweta, Barasch, Jonathan M., Bansal, Shweta, Barkell, Alex, Barwinska, Daria, Basit, Mujeeb, Basta, Jeanine, Bebiak, Jack, Beck, Laurence H., Bender, Filitsa, Berglund, Ashley, Bernard, Lauren, Berrouet, Cecilia, Berry, Brooke, Bjornstad, Petter M., Blanc, Victoria M., Blank, Kristina N., Bledsoe, Sharon, Boada, Patrick, Bogen, Steve, Bomback, Andrew S., Bonevich, Nikole, Borner, Katy, Brown, Keith, Bueckle, Andreas, Burg, Ashley R., Burgess, Adam, Bush, Lakeshia, Bush, William S., Campbell, Catherine E., Campbell, Taneisha, Canetta, Pietro A., Cantley, Lloyd G., Caprioli, Richard M., Carson, Jonas, Chen, Sarah, Chen, Yijiang M., Cheng, Yinghua, Cimino, Jim, Colona, Mia R., Conser, Ninive C., Cooperman, Leslie, Crawford, Dana C., DʼAgati, Vivette D., Dagher, Pierre C., Daniel, Stephen, Daratha, Kenn, de Boer, Ian H., Diettman, Sabine M., Dighe, Ashveena L., Donohoe, Isabel, Dowd, Frederick, Dunn, Kenneth W., Eadon, Michael T., Eddy, Sean, Elder, Michele M., Ferkowicz, Michael J., Frey, Renee, Gadegbeku, Crystal A., Gaut, Joseph P., Gilliam, Matthew, Ginley, Brandon, Gisch, Debora, Goltsev, Yury, Gonzalez-Vicente, Agustin, Greka, Anna, Grewenow, Stephanie M., Hacohen, Nir, Hall, Daniel E., Hansen, Jens, Hayashi, Lynda, He, Cijang, He, Yougqun, Hedayati, S. Susan, Henderson, Joel M., Hendricks, Allen H., Herlitz, Leal, Herr, Bruce W., Himmelfarb, Jonathan, Hodgin, Jeffrey B., Hoofnagle, Andrew N., Hoover, Paul J., Ilori, Titlayo, Iyengar, Ravi, Jain, Sanjay, Jain, Yashvardhan, Janowczyk, Andrew, Jefferson, Nichole, Johansen, Camille, Jolly, Stacey, Kakade, Vijaykumar R., Kellum, John A., Kelly, Katherine J., Kermani, Asra, Kiryluk, Krzysztof, Knight, Richard, Koewler, Robert, Kretzler, Matthias, Kudose, Satoru, Lake, Blue B., Larson, Brandon, Laszik, Zoltan G., Lecker, Stewart H., Lee, Paul J., Lee, Simon C., Lienczewski, Chrysta, Limonte, Christine, Lu, Christopher Y., Lucarelli, Nicholas, Lukowski, Jessica, Luo, Jinghui, Lutnick, Brendon, Ma, Shihong, Madabhushi, Anant, Madhavan, Sethu M., Maikhor, Shana, Mariani, Laura H., Marshall, Jamie L., McClelland, Robyn L., McMahon, Gearoid M., Mehl, Karla, Ferreira, Ricardo Melo, Menez, Steven, Menon, Rajasree, Miller, R. Tyler, Moe, Orson W., Moledina, Dennis, Montellano, Richard, Mooney, Sean D., Morales, Martha Catalina, Mukatash, Tariq, Murugan, Raghavan, Nam, Yunbi, Nguyen, Jane, Nolan, Garry, Oʼtoole, John, Oliver, George (Holt), Onul, Ingrid, Otto, Edgar, Palevsky, Paul M., Palmer, Ellen, Pamreddy, Annapurna, Parikh, Chirag R., Parikh, Samir, Park, Christopher, Park, Harold, Pasa-Tolic, Ljiljana, Patel, Jiten, Patterson, Nathan, Phuong, Jim, Pillai, Anil, Pinkeney, Roy, Poggio, Emilio, Pollack, Ari, Prasad, Pottumarthi, Pyle, Laura, Quardokus, Ellen M., Randhawa, Parmjeet, Rauchman, Michael I., Record, Elizabeth, Rennke, Helmut, Rezaei, Kasra, Rike, Adele, Rivera, Marcelino, Roberts, Glenda V., Rosas, Sylvia E., Rosenberg, Avi, Rosengart, Matthew, Rovin, Brad, Roy, Neil, Sabatello, Maya, Sambandam, Kamalanathan, Sarder, Pinaki, Sarkisova, Natalya, Sarwal, Minnie, Saul, John, Schaub, Jennifer, Schmidt, Insa, Sealfon, Rachel, Sedor, John, Sendrey, Dianna, Shang, Ning, Shankland, Stuart, Shapiro, John P., Sharma, Kumar, Sharman, Kavya, Shaw, Melissa M., Shi, Tiffany, Shpigel, Anna, Sigdel, Tara, Slade, Austen, Snyder, Jamie, Spates-Harden, Kassandra, Spraggins, Jeffrey M., Srivastava, Anand, Steck, Becky, Stillman, Isaac, Stutzke, Christy, Su, Jing, Sun, Jennifer, Sutton, Timothy A., Taliercio, Jonathan, Tan, Roderick, Torrealba, Jose, Toto, Robert D., Troyanskaya, Olga, Tublin, Mitchell, Tuttle, Katherine R., Ugwuowo, Ugochukwu, Valerius, M. Todd, Van de Plas, Raf, Varela, German, Vazquez, Miguel, Velickovic, Dusan, Venkatachalam, Manjeri, Verma, Ashish, Victoria-Castro, Angela M., Vijayan, Anitha, Corona-Villalobos, Celia P., Vinovskis, Carissa, Viswanathan, Vidya S., Vita, Tina, Waikar, Sushrut, Wang, Ashley, Wang, Ruikang, Wang, Nancy, Weins, Astrid, Wen, Natasha, Wen, Yumeng, Wilcox, Adam, Williams, James C., Jr., Kayleen Williams, Williams, Mark, Wilson, Francis P., Winfree, Seth, Winters, James, Wofford, Stephanie, Wong, Aaron, Woodle, E. Steve, Xiong, Yuguang, Xu, Alan, Yadati, Pranav, Ye, Hongping, Yu, Guanghao, Zhang, Dianbo, Zhang, Guanshi, and Zhang, Kun

Published
2024
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10. N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model

Author

Stefano Suzzi, Tommaso Croese, Adi Ravid, Or Gold, Abbe R. Clark, Sedi Medina, Daniel Kitsberg, Miriam Adam, Katherine A. Vernon, Eva Kohnert, Inbar Shapira, Sergey Malitsky, Maxim Itkin, Alexander Brandis, Tevie Mehlman, Tomer M. Salame, Sarah P. Colaiuta, Liora Cahalon, Michal Slyper, Anna Greka, Naomi Habib, and Michal Schwartz

Subjects
Science
Abstract

Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.

Published
2023
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11. FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Author

Wieder, Nicolas, Fried, Juliana Coraor, Kim, Choah, Sidhom, Eriene-Heidi, Brown, Matthew R., Marshall, Jamie L., Arevalo, Carlos, Dvela-Levitt, Moran, Kost-Alimova, Maria, Sieber, Jonas, Gabriel, Katlyn R., Pacheco, Julian, Clish, Clary, Abbasi, Hamdah Shafqat, Singh, Shantanu, Rutter, Justine C., Therrien, Martine, Yoon, Haejin, Lai, Zon Weng, Baublis, Aaron, Subramanian, Renuka, Devkota, Ranjan, Small, Jonnell, Sreekanth, Vedagopuram, Han, Myeonghoon, Lim, Donghyun, Carpenter, Anne E., Flannick, Jason, Finucane, Hilary, Haigis, Marcia C., Claussnitzer, Melina, Sheu, Eric, Stevens, Beth, Wagner, Bridget K., Choudhary, Amit, Shaw, Jillian L., Pablo, Juan Lorenzo, and Greka, Anna

Published
2023
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12. The Human Cell Atlas White Paper

Author

Regev, Aviv, Teichmann, Sarah, Rozenblatt-Rosen, Orit, Stubbington, Michael, Ardlie, Kristin, Amit, Ido, Arlotta, Paola, Bader, Gary, Benoist, Christophe, Biton, Moshe, Bodenmiller, Bernd, Bruneau, Benoit, Campbell, Peter, Carmichael, Mary, Carninci, Piero, Castelo-Soccio, Leslie, Clatworthy, Menna, Clevers, Hans, Conrad, Christian, Eils, Roland, Freeman, Jeremy, Fugger, Lars, Goettgens, Berthold, Graham, Daniel, Greka, Anna, Hacohen, Nir, Haniffa, Muzlifah, Helbig, Ingo, Heuckeroth, Robert, Kathiresan, Sekar, Kim, Seung, Klein, Allon, Knoppers, Bartha, Kriegstein, Arnold, Lander, Eric, Lee, Jane, Lein, Ed, Linnarsson, Sten, Macosko, Evan, MacParland, Sonya, Majovski, Robert, Majumder, Partha, Marioni, John, McGilvray, Ian, Merad, Miriam, Mhlanga, Musa, Naik, Shalin, Nawijn, Martijn, Nolan, Garry, Paten, Benedict, Pe'er, Dana, Philippakis, Anthony, Ponting, Chris, Quake, Steve, Rajagopal, Jayaraj, Rajewsky, Nikolaus, Reik, Wolf, Rood, Jennifer, Saeb-Parsy, Kourosh, Schiller, Herbert, Scott, Steve, Shalek, Alex, Shapiro, Ehud, Shin, Jay, Skeldon, Kenneth, Stratton, Michael, Streicher, Jenna, Stunnenberg, Henk, Tan, Kai, Taylor, Deanne, Thorogood, Adrian, Vallier, Ludovic, van Oudenaarden, Alexander, Watt, Fiona, Weicher, Wilko, Weissman, Jonathan, Wells, Andrew, Wold, Barbara, Xavier, Ramnik, Zhuang, Xiaowei, and Committee, Human Cell Atlas Organizing

Subjects
Quantitative Biology - Tissues and Organs
Abstract

The Human Cell Atlas (HCA) will be made up of comprehensive reference maps of all human cells - the fundamental units of life - as a basis for understanding fundamental human biological processes and diagnosing, monitoring, and treating disease. It will help scientists understand how genetic variants impact disease risk, define drug toxicities, discover better therapies, and advance regenerative medicine. A resource of such ambition and scale should be built in stages, increasing in size, breadth, and resolution as technologies develop and understanding deepens. We will therefore pursue Phase 1 as a suite of flagship projects in key tissues, systems, and organs. We will bring together experts in biology, medicine, genomics, technology development and computation (including data analysis, software engineering, and visualization). We will also need standardized experimental and computational methods that will allow us to compare diverse cell and tissue types - and samples across human communities - in consistent ways, ensuring that the resulting resource is truly global. This document, the first version of the HCA White Paper, was written by experts in the field with feedback and suggestions from the HCA community, gathered during recent international meetings. The White Paper, released at the close of this yearlong planning process, will be a living document that evolves as the HCA community provides additional feedback, as technological and computational advances are made, and as lessons are learned during the construction of the atlas.

Published
2018

13. A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis

Author

Sung-Hee Yoon, Mark B. Meyer, Carlos Arevalo, Murat Tekguc, Chengcheng Zhang, Jialiang S. Wang, Christian D. Castro Andrade, Katelyn Strauss, Tadatoshi Sato, Nancy A. Benkusky, Seong Min Lee, Rebecca Berdeaux, Marc Foretz, Thomas B. Sundberg, Ramnik J. Xavier, Charles H. Adelmann, Daniel J. Brooks, Anthony Anselmo, Ruslan I. Sadreyev, Ivy A. Rosales, David E. Fisher, Navin Gupta, Ryuji Morizane, Anna Greka, J. Wesley Pike, Michael Mannstadt, and Marc N. Wein

Subjects
Bone Biology, Nephrology, Medicine
Abstract

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor–inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease–mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.

Published
2023
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14. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Author

Köttgen, Anna, Cornec-Le Gall, Emilie, Halbritter, Jan, Kiryluk, Krzysztof, Mallett, Andrew J., Parekh, Rulan S., Rasouly, Hila Milo, Sampson, Matthew G., Tin, Adrienne, Antignac, Corinne, Ars, Elisabet, Bergmann, Carsten, Bleyer, Anthony J., Bockenhauer, Detlef, Devuyst, Olivier, Florez, Jose C., Fowler, Kevin J., Franceschini, Nora, Fukagawa, Masafumi, Gale, Daniel P., Gbadegesin, Rasheed A., Goldstein, David B., Grams, Morgan E., Greka, Anna, Gross, Oliver, Guay-Woodford, Lisa M., Harris, Peter C., Hoefele, Julia, Hung, Adriana M., Knoers, Nine V.A.M., Kopp, Jeffrey B., Kretzler, Matthias, Lanktree, Matthew B., Lipska-Ziętkiewicz, Beata S., Nicholls, Kathleen, Nozu, Kandai, Ojo, Akinlolu, Parsa, Afshin, Pattaro, Cristian, Pei, York, Pollak, Martin R., Rhee, Eugene P., Sanna-Cherchi, Simone, Savige, Judy, Sayer, John A., Scolari, Francesco, Sedor, John R., Sim, Xueling, Somlo, Stefan, Susztak, Katalin, Tayo, Bamidele O., Torra, Roser, van Eerde, Albertien M., Weinstock, André, Winkler, Cheryl A., Wuttke, Matthias, Zhang, Hong, King, Jennifer M., Cheung, Michael, Jadoul, Michel, Winkelmayer, Wolfgang C., and Gharavi, Ali G.

Published
2022
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16. Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution

Author

Ahmad Halawi, Abdullah B. El Kurdi, Katherine A. Vernon, Zhabiz Solhjou, John Y. Choi, Anis J. Saad, Nour K. Younis, Rania Elfekih, Mostafa Tawfeek Mohammed, Christa A. Deban, Astrid Weins, Reza Abdi, Leonardo V. Riella, Sasha A. De Serres, Paolo Cravedi, Anna Greka, Pierre Khoueiry, and Jamil R. Azzi

Subjects
graft rejection, kidney transplantation, single-cell analysis, cellular microenvironment, alloimmunity, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundKidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects.MethodsTo understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions.ResultsPathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions.ConclusionOur data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.

Published
2023
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18. A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis

Author

Yoon, Sung-Hee, Meyer, Mark B., Arevalo, Carlos, Tekguc, Murat, Zhang, Chengcheng, Wang, Jialiang S., Andrade, Christian D. Castro, Strauss, Katelyn, Sato, Tadatoshi, Benkusky, Nancy A., Lee, Seong Min, Berdeaux, Rebecca, Foretz, Marc, Sundberg, Thomas B., Xavier, Ramnik J., Adelmann, Charles H., Brooks, Daniel J., Anselmo, Anthony, Sadreyev, Ruslan I., Rosales, Ivy A., Fisher, David E., Gupta, Navin, Morizane, Ryuji, Greka, Anna, Pike, J. Wesley, Mannstad, Michael, and Wein, Marc N.

Subjects
Parathyroid hormone -- Health aspects, Gene expression -- Health aspects, Cellular signal transduction -- Health aspects, Bone diseases -- Genetic aspects -- Development and progression -- Care and treatment, Kidney diseases -- Genetic aspects -- Development and progression -- Care and treatment, Cytochrome P-450 -- Health aspects, Health care industry
Abstract

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25- vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD., Introduction Vitamin D plays a critical role in bone and mineral metabolism and also controls other physiologic and pathophysiologic processes, including skeletal muscle function, reproductive health, cancer risk and progression, [...]

Published
2023
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20. Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis

Author

Knight, Richard, Lecker, Stewart H., Stillman, Isaac, Bogen, Steve, Amodu, Afolarin A., Ilori, Titlayo, Maikhor, Shana, Schmidt, Insa M., Beck, Laurence H., Henderson, Joel M., Onul, Ingrid, Verma, Ashish, McMahon, Gearoid M., Valerius, M. Todd, Waikar, Sushrut, Weins, Astrid, Colona, Mia R., Greka, Anna, Hacohen, Nir, Hoover, Paul J., Marshall, Jamie L., Aulisio, Mark, Chen, Yijiang M., Janowczyk, Andrew, Jayapandian, Catherine, Viswanathan, Vidya S., Bush, William S., Crawford, Dana C., Madabhushi, Anant, Bush, Lakeshia, Cooperman, Leslie, Gonzalez-Vicente, Agustin, Herlitz, Leal, Jolly, Stacey, Nguyen, Jane, O’toole, John, Palmer, Ellen, Poggio, Emilio, Sedor, John, Sendrey, Dianna, Spates-Harden, Kassandra, Taliercio, Jonathan, Bjornstad, Petter M., Pyle, Laura, Vinovskis, Carissa, Appelbaum, Paul, Balderes, Olivia, Barasch, Jonathan M., Bomback, Andrew S., Canetta, Pietro A., D’Agati, Vivette D., Kiryluk, Krzysztof, Kudose, Satoru, Mehl, Karla, Shang, Ning, Bansal, Shweta, Alexandrov, Theodore, Rennke, Helmut, El-Achkar, Tarek M., Barwinska, Daria, Bledso, Sharon, Borner, Katy, Bueckle, Andreas, Cheng, Yinghua, Dagher, Pierre C., Dunn, Kenneth W., Eadon, Michael T., Ferkowicz, Michael J., Herr, Bruce W., Kelly, Katherine J., Ferreira, Ricardo Melo, Quardokus, Ellen M., Record, Elizabeth, Rivera, Marcelino, Su, Jing, Sutton, Timothy A., Williams, James C., Jr., Winfree, Seth, Jain, Yashvardhan, Menez, Steven, Parikh, Chirag R., Rosenberg, Avi, Corona-Villalobos, Celia P., Wen, Yumeng, Johansen, Camille, Rosas, Sylvia E., Roy, Neil, Sun, Jennifer, Williams, Mark, Azeloglu, Evren U., Hansen, Jens, He, Cijang, Iyengar, Ravi, Xiong, Yuguang, Prasad, Pottumarthi, Srivastava, Anand, Madhavan, Sethu M., Parikh, Samir, Rovin, Brad, Shapiro, John P., Anderton, Christopher R., Lukowski, Jessica, Pasa-Tolic, Ljiljana, Velickovic, Dusan, Oliver, George (Holt), Ardayfio, Joseph, Bebiak, Jack, Brown, Keith, Campbell, Taneisha, Campbell, Catherine E., Hayashi, Lynda, Jefferson, Nichole, Roberts, Glenda V., Saul, John, Shpigel, Anna, Stutzke, Christy, Koewler, Robert, Pinkeney, Roy, Sealfon, Rachel, Troyanskaya, Olga, Wong, Aaron, Tuttle, Katherine R., Pollack, Ari, Goltsev, Yury, Ginley, Brandon, Lucarelli, Nicholas, Lutnick, Brendon, Sarder, Pinaki, Lake, Blue B., Zhang, Kun, Boada, Patrick, Laszik, Zoltan G., Nolan, Garry, Anjani, Kavya, Sarwal, Minnie, Mukatash, Tariq, Sigdel, Tara, Alloway, Rita R., Burg, Ashley R., Lee, Paul J., Rike, Adele, Shi, Tiffany, Woodle, E. Steve, Ascani, Heather, Balis, Ulysses G.J., Blanc, Victoria M., Conser, Ninive C., Eddy, Sean, Frey, Renee, He, Yougqun, Hodgin, Jeffrey B., Kretzler, Matthias, Lienczewski, Chrysta, Luo, Jinghui, Mariani, Laura H., Menon, Rajasree, Otto, Edgar, Schaub, Jennifer, Steck, Becky, Elder, Michele M., Gilliam, Matthew, Hall, Daniel E., Murugan, Raghavan, Palevsky, Paul M., Randhawa, Parmjeet, Rosengart, Matthew, Tublin, Mitchell, Vita, Tina, Winters, James, Kellum, John A., Alpers, Charles E., Berglund, Ashley, Berry, Brooke, Blank, Kristina N., Carson, Jonas, Daniel, Stephen, De Boer, Ian H., Dighe, Ashveena L., Dowd, Frederick, Grewenow, Stephanie M., Himmelfarb, Jonathan, Hoofnagle, Andrew N., Limonte, Christine, McClelland, Robyn L., Mooney, Sean D., Rezaei, Kasra, Shankland, Stuart, Snyder, Jamie, Wang, Ruikang, Wilcox, Adam, Williams, Kayleen, Park, Christopher, Montellano, Richard, Pamreddy, Annapurna, Sharma, Kumar, Venkatachalam, Manjeri, Ye, Hongping, Zhang, Guanshi, Basit, Mujeeb, Hedayati, S. Susan, Kermani, Asra, Lee, Simon C., Lu, Christopher Y., Miller, R. Tyler, Moe, Orson W., Patel, Jiten, Pillai, Anil, Sambandam, Kamalanathan, Torrealba, Jose, Toto, Robert D., Vazquez, Miguel, Wang, Nancy, Wen, Natasha, Zhang, Dianbo, Park, Harold, Caprioli, Richard M., Patterson, Nathan, Sharman, Kavya, Spraggins, Jeffrey M., Van de Plas, Raf, Basta, Jeanine, Diettman, Sabine M., Gaut, Joseph P., Jain, Sanjay, Rauchman, Michael I., Vijayan, Anitha, Cantley, Lloyd G., Kakade, Vijaykumar R., Moledina, Dennis, Shaw, Melissa M., Ugwuowo, Ugochukwu, Wilson, Francis P., Arora, Tanima, Kestenbaum, Bryan R., Alexopoulos, Leonidas G., Palsson, Ragnar, Liu, Jing, Stillman, Isaac E., Rennke, Helmut G., Vaidya, Vishal S., Wu, Haojia, Humphreys, Benjamin D., and Waikar, Sushrut S.

Published
2021
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23. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1

Author

Olinger, Eric, Hofmann, Patrick, Kidd, Kendrah, Dufour, Inès, Belge, Hendrica, Schaeffer, Céline, Kipp, Anne, Bonny, Olivier, Deltas, Constantinos, Demoulin, Nathalie, Fehr, Thomas, Fuster, Daniel G., Gale, Daniel P., Goffin, Eric, Hodaňová, Kateřina, Huynh-Do, Uyen, Kistler, Andreas, Morelle, Johann, Papagregoriou, Gregory, Pirson, Yves, Sandford, Richard, Sayer, John A., Torra, Roser, Venzin, Christina, Venzin, Reto, Vogt, Bruno, Živná, Martina, Greka, Anna, Dahan, Karin, Rampoldi, Luca, Kmoch, Stanislav, Bleyer, Anthony J., Sr., and Devuyst, Olivier

Published
2020
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24. Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases

Author

Bleyer, Anthony J., Kidd, Kendrah, Robins, Victoria, Martin, Lauren, Taylor, Abbigail, Santi, Annie, Tsoumas, Georgeanna, Hunt, Alese, Swain, Elizabeth, Abbas, Marwan, Akinbola, Ebun, Vidya, Sri, Moossavi, Shahriar, Bleyer, Anthony J., Jr., Živná, Martina, Hartmannová, Hana, Hodaňová, Kateřina, Vyleťal, Petr, Votruba, Miroslav, Harden, Maegan, Blumenstiel, Brendan, Greka, Anna, and Kmoch, Stanislav

Published
2020
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25. Principles of Spatial Transcriptomics Analysis: A Practical Walk-Through in Kidney Tissue

Author

Teia Noel, Qingbo S. Wang, Anna Greka, and Jamie L. Marshall

Subjects
slide-seqV2, spatial transcriptomics, kidney spatial transcriptomics, slide-seq, kidney transcriptomics, Physiology, QP1-981
Abstract

Spatial transcriptomic technologies capture genome-wide readouts across biological tissue space. Moreover, recent advances in this technology, including Slide-seqV2, have achieved spatial transcriptomic data collection at a near-single cell resolution. To-date, a repertoire of computational tools has been developed to discern cell type classes given the transcriptomic profiles of tissue coordinates. Upon applying these tools, we can explore the spatial patterns of distinct cell types and characterize how genes are spatially expressed within different cell type contexts. The kidney is one organ whose function relies upon spatially defined structures consisting of distinct cellular makeup. Thus, the application of Slide-seqV2 to kidney tissue has enabled us to elucidate spatially characteristic cellular and genetic profiles at a scale that remains largely unexplored. Here, we review spatial transcriptomic technologies, as well as computational approaches for cell type mapping and spatial cell type and transcriptomic characterizations. We take kidney tissue as an example to demonstrate how the technologies are applied, while considering the nuances of this architecturally complex tissue.

Published
2022
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27. Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Author

Dvela-Levitt, Moran, Kost-Alimova, Maria, Emani, Maheswarareddy, Kohnert, Eva, Thompson, Rebecca, Sidhom, Eriene-Heidi, Rivadeneira, Ana, Sahakian, Nareh, Roignot, Julie, Papagregoriou, Gregory, Montesinos, Monica S., Clark, Abbe R., McKinney, David, Gutierrez, Juan, Roth, Mark, Ronco, Lucienne, Elonga, Esther, Carter, Todd A., Gnirke, Andreas, Melanson, Michelle, Hartland, Kate, Wieder, Nicolas, Hsu, Jane C.-H., Deltas, Constantinos, Hughey, Rebecca, Bleyer, Anthony J., Kmoch, Stanislav, Živná, Martina, Barešova, Veronika, Kota, Savithri, Schlondorff, Johannes, Heiman, Myriam, Alper, Seth L., Wagner, Florence, Weins, Astrid, Golub, Todd R., Lander, Eric S., and Greka, Anna

Published
2019
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28. Protein N-Glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease

Author

Veličković, Dušan, Shapiro, John P., Parikh, Samir V., Rovin, Brad, Toto, Robert D., Vazquez, Miguel A., Poggio, Emilio D., O'Toole, John F., Sedor, John R., Alexandrov, Theodore, Jain, Sanjay, Bitzer, Markus, Hodgin, Jeffrey, Veličković, Marija, Sharma, Kumar, Anderton, Christopher R., Adeyi, Oyedele A., Alakwaa, Fadhl, Alexandrov, Theodore, Allen, Jamie L., Alpers, Charles E., Alvear, Alison Bunio, Ambekar, Akhil, Ancheta, Joed, Anderton, Christopher R., Angus, Sophia A., Anjani, Kavya, Appelbaum, Paul S., Ardayfio, Joseph, Arora, Tanima, Ascani, Heather K., Asghari, Mahla, El-Achkar, Tarek M., Athar, Humra, Atta, Mohamed G., Aulisio, Mark P., Aw, Stephanie J., Azeloglu, Evren U., Bagne, Cathy A., Balderes, Olivia, Balis, Ulysses G.J., Barasch, Jonathan, Barisoni, Laura, Barwinska, Daria, Basta, Jeannine, Bebiak, Jack, Beck, Laurence H., Berge, Jerica M., Berglund, Ashley C., Bernard, Lauren, Berry, Brooke, Beyda, David H., Bhanushali, Jini Ashok, Bitzer, Markus, Bjornstad, Petter, Blanc, Victoria M., Blank, Kristina N., Bledsoe, Sharon B., Bogen, Steve, Bomback, Andrew S., Bonevich, Nikole, Border, Samuel, Börner, Katy, Bowen, William S., Boys, Charlotte, Bracamonte, Erika R., Bream, Peter R., Brosius, Frank C., Brown, Keith D., Budiman, Tifanny, Bueckle, Andreas, Bui, J.T., James, T., Burg, Ashley R., Burgess, Adam, Bush, Lakeshia, Bush, William S., Cai, Qi, Calixte, Marie Florence, Cameron-Wheeler, Tashas, Campbell, Kirk N, Campbell, Taneisha, Campbell, Catherine, Campos, Baltazar, Canetta, Pietro A., Cantley, Lloyd G, Caramori, M. Luiza, Carmona-Powell, Eunice, Carson, Jonas M, Chan, Lili, Chen, Sarah W, Chen, Yijiang, Cheng, Ying-Hua, Bejarano, Maria Chilo, Choe, Kisurb, Cimino, James G., Coca, Steven G., Coleman, Alyson, Colley, Madeline E., Collie, Mary M., Colona, Mia R., Commander, Clayton W., Conlon, Kristine, Conser, Ninive, Cooperman, Leslie, Corona-Villalobos, Celia P., Crawford, Dana C., Creger, Nathan, Cuevas-Rios, Yarieli, D'Agati, Vivette ., Dagher, Pierre c., de Boer, Ian H., de Caestecker, M.P, de Cos, Marina, Gonçalves, Joana P., Dekker, Matthew, Demeke, Dawit, Dighe, Ashveena L, Ding, Yanli, Djambazova, Katerina V., Donohoe, Isabel, Dowd, Frederick, Drawz, P.E., Dufresne, Martin, Dull, Rachel, Dunn, Kenneth W., Duran, Daniel Damian, Eadon, Michael T, Eddy, Sean, Elder, Michele M, Fallegger, Robin, Farrow, Melissa A, Ferkowicz, Michael, Fine, Derek M., Flanagan, Siobhan M., Fogo, Agnes B., Fox, Monica L., Frey, Renee, Froment, Anne, Gaba, Ron C., Gadegbeku, Crystal A, Gaut, Joseph P., Gehlenborg, Nils, Geraghty, Molly C, Ghag, Reetika, Gilliam, Matthew, Ginley, Brandon, Gisch, Debora, Gordon, Ronald E., Gorman, Brittney L., Greka, Anna, Grewenow, Stephanie M., Gurung, Bhupendra Kumar, Guthrie, Leah, Hacohen, Nir, Haddad, Samuel, Hall, Daniel E., Hansen, Jens, Harindhanavudhi, Tasma, Hartman, John, Hayashi, Lynda, Haydak, Jonathan, He, John Cijiang, He, Yongqun, Hedayati, S. Susan, Henderson, Dori, Henderson, Joel M, Hendricks, Allen R, Henshaw, Asari, Herlitz, Leal, Hernandez, Jeanine, Herr, Bruce W., Himmelfarb, Jonathan, Hodgin, Jeffrey B., Hoofnagle, Andrew N, Horowitz, Carol R., Hsieh, E.W.Y., Huynh, Courtney, Iyengar, Ravi, Jain, Sanjay, Janowczyk, Andrew, Jeffers, Vivian, Jefferson, Nichole M., Jennette, J Charles, Johansen, Camille, Jolly, Stacey, Jones, Christopher J., Jones, Jennifer L., Jones, Kiasha, Joyeux, Cienn N., Ju, Wenjun, Judd, Audra M., Kakade, Vijayakumar R, Kakarla, Dhatri, Kaspari, Rachel R., Kaushal, Madhurima, Keefe, Nicole, Keller, Mark S., Kelley, Sara S., Kellum, John A., Kelly, K. J., Kelly, Tanika N., Kermani, Asra, Kiryluk, Krzysztof, Klett, Susan, Knight, Richard A., Knoten, Amanda, Koch, Gina, Koewler, Robert, Kretzler, Matthias, Kruse, Angela R.S., Küchenhoff, Leonie, Lake, Blue B., Lardenoije, Roy, Larson, Astrid, Larson, Brandon G, Lash, James P., Laszik, Zoltan G., Lecker, Stewart H., Lee, Simon C., Lee, Sora, Lefferts, Sean, Li, Xiang, Lienczewski, Chrysta C, Limonte, Christine P, Lucarelli, Nicholas, Lukowski, Jessica, Lutnick, Brendon, Ma, Shihong, Ma, Sisi, Madabhushi, Anant, Maikhor, Shana, Mao, Weiguang, Mariani, Laura H., Markovic, Marina, Marquez, Nicole, Marshall, Jamie L., McAdams, Meredith C, McClelland, Robyn L., McCown, Phillip J., McMahon, Gearoid Michael, McMurray, Amy, Mehl, Karla, Meliambro, Kristin, Ferreira, Ricardo Melo, Mendoza, Katherine, Menez, Steven, Menon, Rajasree, Meza, Natalie, Migas, Lukasz G., Miller, R. Tyler, Mimar, Sayat, Minor, Brittany C, Mody, Priya, Moeckel, Gilbert W., Moledina, D.G., Molina-Guzman, Jenny, Monroy-Trujillo, Jose M, Morales, Alexander, Moreno, Vanessa, Mottl, Amy K., Mukatash, Tariq, Munar, Dane, Murugan, Raghavan, Nachman, Patrick H., Nadkarni, Girish N, Naglah, Ahmed, Nair, Viji, Nam, Yunbi, Narasimhan, R., Nwanne, Gerald, O'Malley, Charles, O'Toole, John F., Toro, Fernanda Ochoa, Oliver, George (Holt), Onul, Ingrid F, Otto, Edgar A., Palevsky, Paul M., Palmer, Ellen, Pamreddy, Annapurna, Parikh, Chirag R., Parikh, Samir V, Park, Christopher, Park, Harold, Paša-Tolić, Ljiljana, Patel, Jiten, Patel, Marissa, Patlis, Boris S., Paul, Anindya S., Phuong, Jimmy, Pillai, Anil, Pinkeney, Roy, Plisiewicz, Alexa, Poggio, Emilio D, Pollack, Ari, Prasad, Pottumarthi V, Pyle, Laura, Quardokus, Ellen M., Quiroga, Arabela, Ragi, Nagarjunachary, Randhawa, Parmjeet, Randle, Teresa, Rao, Via, Rauchman, Michael, Rauwolf, Nicolas J, Reamy, Rebecca, Record, Elizabeth G., Redmond, Devona, Rennke, Helmut, Renteria, Amada, Rezaei, Kasra A, Rhodes, Rosamond, Ricardo, Ana C., Rice, Samuel, Rivera, Marcelino, Roberts, Glenda V., Rosas, R., Sylvia, E., Rose, Michael P., Rosen, Seymour, Rosenberg, Avi Z., Rosenberg, Michael S., Rosengart, Matthew R., Rovin, Brad H., Roy, Neil, Roy-Chaudhury, Prabir, Rubinsky, Melissa D., Sabo, Angela R., Saez-Rodriguez, Julio, Safadi, Sami, Samari, Imane H., Sanora, Ana Celina, Sarder, Pinaki, Sarkisova, Natalya, Sarwal, Minnie M, Saul, John, Saunders, Milda R., Schaub, Jennifer A., Schmidt, IM, Scott, Raymond, Scroggins, Aaron, Sealfon, Rachel S. G., Sedor, John R., Sendrey, Dianna, Setty, Suman, Shah, Sonya, Shariff, Saad Mohammed, Sharma, Kumar, Shaw, Melissa M., Sigdel, Tara K, Silva, Paolo S., Snyder, Jaime, Snyder, Michelle L., Spates-Harden, Kassandra, Sperati, C. John, Spraggins, Jeffrey M., Srivastava, Anand, Stashevsky, Jennifer, Steck, Becky, Stillman, Isaac E, Stutzke, Christy, Subramanian, Lalita, Sun, Jennifer K., Rajan, Sandhya Sundar, Sutton, Timothy A., Taliercio, Jonathan J, Tan, Roderick, Tanevski, Jovan, Thajudeen, Bijin, Thurman, Joshua M., Tokita, Joji, Torrealba, Jose R., Toto, Robert D, Tout, Haneen, Troyanskaya, Olga G, Tsosie, Rebecca, Turner, Jeffrey M, Tuttle, Katherine R., Ugwuowo, Ugochukwu, Upadhyay, Ashish, Valerius, M. Todd, Van de Plas, Raf, Varela, German, Vazquez, Miguel A., Velickovic, Dusan, Venkatachalam, Manjeri, Verdoes, Abraham, Verma, Ashish, Victoria-Castro, Angela M., Vijayan, Anitha, Villalobos, Alexander, Viloria, Noralinda B., Vinovskis, Carissa, Vita, Tina, Waikar, Sushrut S., Wang, Ashley R., Wang, Bangchen, Wang, Nancy, Wang, Ruikang, Wangperawong, Artit, Ward, Stephen C, Warfield, Curtis, Weins, Astrid, Wen, Natasha, Wen, Yumeng, Wilcox, Adam, Williams, James C., Williams, Kayleen, Williams, Mark E., Wilson, F. Perry, Winfree, Seth, Winters, James, Wofford, Stephanie, Wolf, Susan M., Wong, Aaron, Woodhead, Gregory, Wright, Devin M., Wright, Zach, Wright, Zoe, Wrobel, Julia, Xing, Fuyong, Xu, Alan, Yadati, Pranav, Ye, Hongping, Young, Bessie A., Yu, Guanghao, Mon-Wei Yu, Samuel, Zeinoun, Gabriel, Zeitler, Evan M., Zhang, Bo, Zhang, Guanshi, and Zhang, Yi

Published
2024
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29. TRPC5 Channel Inhibition Protects Podocytes in Puromycin-Aminonucleoside Induced Nephrosis Models

Author

Yiming Zhou, Choah Kim, Juan Lorenzo B. Pablo, Fan Zhang, Ji Yong Jung, Li Xiao, Silvana Bazua-Valenti, Maheswarareddy Emani, Corey R. Hopkins, Astrid Weins, and Anna Greka

Subjects
TRPC5 channel, calcium signaling, Rac1, podocyte, kidney disease, Medicine (General), R5-920
Abstract

Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of kidney disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated rats, human iPSC-derived podocytes, and kidney organoids. We first established that systemic administration of the TRPC5 inhibitor AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis rats, an established model of podocyte injury. TRPC5 current was recorded in the human iPSC-derived podocytes and was blocked by AC1903. PAN treatment caused podocyte injury in human iPSC-derived podocytes and kidney organoids. Inhibition of TRPC5 channels reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of TRPC5 channel inhibition in puromycin-aminonucleoside induced nephrosis models, highlighting the potential of this therapeutic strategy for patients.

Published
2021
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30. Single cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation

Author

Ayshwarya Subramanian, Eriene-Heidi Sidhom, Maheswarareddy Emani, Katherine Vernon, Nareh Sahakian, Yiming Zhou, Maria Kost-Alimova, Michal Slyper, Julia Waldman, Danielle Dionne, Lan T. Nguyen, Astrid Weins, Jamie L. Marshall, Orit Rosenblatt-Rosen, Aviv Regev, and Anna Greka

Subjects
Science
Abstract

How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.

Published
2019
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33. Abatacept in B7-1–Positive Proteinuric Kidney Disease

Author

Yu, Chih-Chuan, Fornoni, Alessia, Weins, Astrid, Hakroush, Samy, Maiguel, Dony, Sageshima, Junichiro, Chen, Linda, Ciancio, Gaetano, Faridi, Mohd Hafeez, Behr, Daniel, Campbell, Kirk N, Chang, Jer-Ming, Chen, Hung-Chun, Oh, Jun, Faul, Christian, Arnaout, M Amin, Fiorina, Paolo, Gupta, Vineet, Greka, Anna, Burke, George W, and Mundel, Peter

Subjects
Kidney Disease, Rare Diseases, Renal and urogenital, Abatacept, Adolescent, Adult, B7-1 Antigen, Biomarkers, Child, Female, Glomerulosclerosis, Focal Segmental, Humans, Immunoconjugates, Male, Podocytes, Proteinuria, Young Adult, Medical and Health Sciences, General & Internal Medicine
Abstract

Abatacept (cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein [CTLA-4-Ig]) is a costimulatory inhibitor that targets B7-1 (CD80). The present report describes five patients who had focal segmental glomerulosclerosis (FSGS) (four with recurrent FSGS after transplantation and one with primary FSGS) and proteinuria with B7-1 immunostaining of podocytes in kidney-biopsy specimens. Abatacept induced partial or complete remissions of proteinuria in these patients, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies. Our data indicate that abatacept may stabilize β1-integrin activation in podocytes and reduce proteinuria in patients with B7-1-positive glomerular disease.

Published
2013

34. Mechanisms of Protein Trafficking and Quality Control in the Kidney and Beyond

Author

Jillian L. Shaw, Juan Lorenzo Pablo, and Anna Greka

Subjects
Physiology
Abstract

Numerous trafficking and quality control pathways evolved to handle the diversity of proteins made by eukaryotic cells. However, at every step along the biosynthetic pathway, there is the potential for quality control system failure. This review focuses on the mechanisms of disrupted proteostasis. Inspired by diseases caused by misfolded proteins in the kidney (mucin 1 and uromodulin), we outline the general principles of protein biosynthesis, delineate the recognition and degradation pathways targeting misfolded proteins, and discuss the role of cargo receptors in protein trafficking and lipid homeostasis. We also discuss technical approaches including live-cell fluorescent microscopy, chemical screens to elucidate trafficking mechanisms, multiplexed single-cell CRISPR screening platforms to systematically delineate mechanisms of proteostasis, and the advancement of novel tools to degrade secretory and membrane-associated proteins. By focusing on components of trafficking that go awry, we highlight ongoing efforts to understand fundamental mechanisms of disrupted proteostasis and implications for the treatment of human proteinopathies.

Published
2023
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35. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Author

Zhou, Yiming, Castonguay, Philip, Sidhom, Eriene-Heidi, Clark, Abbe R., Dvela-Levitt, Moran, Kim, Sookyung, Sieber, Jonas, Wieder, Nicolas, Jung, Ji Yong, Andreeva, Svetlana, Reichardt, Jana, Dubois, Frank, Hoffmann, Sigrid C., Basgen, John M., Montesinos, Mónica S., Weins, Astrid, Johnson, Ashley C., Lander, Eric S., Garrett, Michael R., Hopkins, Corey R., and Greka, Anna

Published
2017

38. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

Author

Li Xiao, Xiaoxuan Xu, Fan Zhang, Ming Wang, Yan Xu, Dan Tang, Jiahui Wang, Yan Qin, Yu Liu, Chengyuan Tang, Liyu He, Anna Greka, Zhiguang Zhou, Fuyou Liu, Zheng Dong, and Lin Sun

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK. Keywords: Mitoq, Diabetic kidney disease, Mitophagy, Tubular

Published
2017
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40. Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

Author

Massachusetts Institute of Technology. Department of Biology, Eraslan, Gökcen, Drokhlyansky, Eugene, Anand, Shankara, Fiskin, Evgenij, Subramanian, Ayshwarya, Slyper, Michal, Wang, Jiali, Van Wittenberghe, Nicholas, Rouhana, John M, Waldman, Julia, Ashenberg, Orr, Lek, Monkol, Dionne, Danielle, Win, Thet Su, Cuoco, Michael S, Kuksenko, Olena, Tsankov, Alexander M, Branton, Philip A, Marshall, Jamie L, Greka, Anna, Getz, Gad, Segrè, Ayellet V, Aguet, François, Rozenblatt-Rosen, Orit, Ardlie, Kristin G, Regev, Aviv, Massachusetts Institute of Technology. Department of Biology, Eraslan, Gökcen, Drokhlyansky, Eugene, Anand, Shankara, Fiskin, Evgenij, Subramanian, Ayshwarya, Slyper, Michal, Wang, Jiali, Van Wittenberghe, Nicholas, Rouhana, John M, Waldman, Julia, Ashenberg, Orr, Lek, Monkol, Dionne, Danielle, Win, Thet Su, Cuoco, Michael S, Kuksenko, Olena, Tsankov, Alexander M, Branton, Philip A, Marshall, Jamie L, Greka, Anna, Getz, Gad, Segrè, Ayellet V, Aguet, François, Rozenblatt-Rosen, Orit, Ardlie, Kristin G, and Regev, Aviv

Abstract

Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.

Published
2023

42. Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

Author

Sidhom, Eriene-Heidi, Kim, Choah, Kost-Alimova, Maria, Ting, May Theng, Keller, Keith, Avila-Pacheco, Julian, Watts, Andrew J.B., Vernon, Katherine A., Marshall, Jamie L., Reyes-Bricio, Estefania, Racette, Matthew, Wieder, Nicolas, Kleiner, Giulio, Grinkevich, Elizabeth J., Chen, Fei, Weins, Astrid, Clish, Clary B., Shaw, Jillian L., Quinzii, Catarina M., and Greka, Anna

Subjects
Enzymes -- Regulation, Ubiquinones -- Health aspects, Cellular signal transduction -- Genetic aspects -- Health aspects, Kidney diseases -- Genetic aspects -- Development and progression -- Care and treatment, Health care industry
Abstract

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of [Pdss2.sup.kd/kd] mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in [Pdss2.sup.kd/kd] mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA- mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases., Introduction Deep mechanistic understanding of genetically defined diseases can provide insight into fundamental biology and potential therapeutic targets for the treatment of rare and prevalent diseases (1-7). Mitochondrial cytopathies are [...]

Published
2021
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44. Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution

Author

Halawi, Ahmad, primary, El Kurdi, Abdullah B., additional, Vernon, Katherine A., additional, Solhjou, Zhabiz, additional, Choi, John Y., additional, Saad, Anis J., additional, Younis, Nour K., additional, Elfekih, Rania, additional, Mohammed, Mostafa Tawfeek, additional, Deban, Christa A., additional, Weins, Astrid, additional, Abdi, Reza, additional, Riella, Leonardo V., additional, De Serres, Sasha A., additional, Cravedi, Paolo, additional, Greka, Anna, additional, Khoueiry, Pierre, additional, and Azzi, Jamil R., additional

Published
2023
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45. FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Author

Wieder, Nicolas, primary, Fried, Juliana Coraor, additional, Kim, Choah, additional, Sidhom, Eriene-Heidi, additional, Brown, Matthew R., additional, Marshall, Jamie L., additional, Arevalo, Carlos, additional, Dvela-Levitt, Moran, additional, Kost-Alimova, Maria, additional, Sieber, Jonas, additional, Gabriel, Katlyn R., additional, Pacheco, Julian, additional, Clish, Clary, additional, Abbasi, Hamdah Shafqat, additional, Singh, Shantanu, additional, Rutter, Justine, additional, Therrien, Martine, additional, Yoon, Haejin, additional, Lai, Zon Weng, additional, Baublis, Aaron, additional, Subramanian, Renuka, additional, Devkota, Ranjan, additional, Small, Jonnell, additional, Sreekanth, Vedagopuram, additional, Han, Myeonghoon, additional, Lim, Donghyun, additional, Carpenter, Anne E., additional, Flannick, Jason, additional, Finucane, Hilary, additional, Haigis, Marcia C., additional, Claussnitzer, Melina, additional, Sheu, Eric, additional, Stevens, Beth, additional, Wagner, Bridget K., additional, Choudhary, Amit, additional, Shaw, Jillian L., additional, Pablo, Juan Lorenzo, additional, and Greka, Anna, additional

Published
2023
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47. FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Author

Nicolas Wieder, Juliana Coraor Fried, Choah Kim, Eriene-Heidi Sidhom, Matthew R. Brown, Jamie L. Marshall, Carlos Arevalo, Moran Dvela-Levitt, Maria Kost-Alimova, Jonas Sieber, Katlyn R. Gabriel, Julian Pacheco, Clary Clish, Hamdah Shafqat Abbasi, Shantanu Singh, Justine Rutter, Martine Therrien, Haejin Yoon, Zon Weng Lai, Aaron Baublis, Renuka Subramanian, Ranjan Devkota, Jonnell Small, Vedagopuram Sreekanth, Myeonghoon Han, Donghyun Lim, Anne E. Carpenter, Jason Flannick, Hilary Finucane, Marcia C. Haigis, Melina Claussnitzer, Eric Sheu, Beth Stevens, Bridget K. Wagner, Amit Choudhary, Jillian L. Shaw, Juan Lorenzo Pablo, and Anna Greka

Subjects
Physiology, Cell Biology, Molecular Biology, Article
Abstract

SummaryCellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.HighlightsFALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effectsFALCON is applicable to many and diverse cell typesA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidityNew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for diseaseC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling

Published
2023
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49. Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis

Author

Mark E. Williams, Katherine R. Tuttle, Jing Liu, Jinghui Luo, Yougqun He, Laura Pyle, Blue B. Lake, Brad H. Rovin, Lynda Hayashi, Yuguang Xiong, Dennis G. Moledina, Andreas Bueckle, Steven Menez, Glenda V. Roberts, Anand Srivastava, Paul Appelbaum, Heather Ascani, Catherine Campbell, Stephanie M. Grewenow, Mark Aulisio, Jennifer Sun, Christopher R. Anderton, Jamie L. Marshall, Sharon Bledso, John P. Shapiro, Theodore Alexandrov, Richard M. Caprioli, Michele Elder, Leslie Cooperman, Shweta Bansal, Lakeshia Bush, Krzysztof Kiryluk, Mitchell Tublin, Olga G. Troyanskaya, Emilio D. Poggio, Kristina N. Blank, Andrew Janowczyk, Paul Hoover, Sabine M. Diettman, R. Tyler Miller, Katy Borner, Leonidas G. Alexopoulos, James Winters, Anant Madabhushi, Haojia Wu, Chirag R. Parikh, Yumeng Wen, Avi Z. Rosenberg, Agustin Gonzalez-Vicente, Leal Herlitz, Keith Brown, Matthew Gilliam, Joseph P. Gaut, Vidya S. Viswanathan, Karla Mehl, Stewart H. Lecker, Pierre C. Dagher, Dana C. Crawford, Camille Johansen, Anna Greka, Tiffany Shi, Ari Pollack, Renee Frey, Kavya Sharman, Isaac E. Stillman, Stuart J. Shankland, Ricardo Melo Ferreira, Jack Bebiak, Jing Su, Matthias Kretzler, Ellen Palmer, Yury Goltsev, Aaron K. Wong, Matthew R. Rosengart, Taneisha Campbell, Tina Vita, Helmut G. Rennke, Nir Hacohen, Satoru Kudose, Christine Limonte, Kun Zhang, Robyn L. McClelland, Ulysses J. Balis, Katherine J. Kelly, Simon Lee, Ninive C. Conser, Adele Rike, Frederick Dowd, Timothy A. Sutton, Steve Bogen, Petter M. Bjornstad, Zoltan Laszik, Dianbo Zhang, Benjamin D. Humphreys, Pinaki Sarder, Jeffrey M. Spraggins, Ravi Iyengar, Marcelino Rivera, Roy Pinkeney, James C. Williams, Tarek M. El-Achkar, Laura H. Mariani, Richard J. Knight, Manjeri A. Venkatachalam, Pietro A. Canetta, Lloyd G. Cantley, Kayleen Williams, Catherine P. Jayapandian, Edgar A. Otto, Jessica Lukowski, Kassandra Spates-Harden, Ashish Verma, John Saul, Tariq Mukatash, Mia R. Colona, Shana Maikhor, Laurence H. Beck, Titlayo Ilori, Charles E. Alpers, Ellen M. Quardokus, Mujeeb Basit, Dušan Veličković, Raf Van de Plas, Jonathan Himmelfarb, Michael T. Eadon, Chrysta Lienczewski, Christopher Y. Lu, Yijiang M. Chen, Kasra Rezaei, Richard Montellano, Pottumarthi V. Prasad, Francis P. Wilson, Christy Stutzke, Jane Nguyen, Kamalanathan K. Sambandam, Miguel A. Vazquez, Vishal S. Vaidya, Vivette D. D'Agati, Patrick Boada, Adam Wilcox, Astrid Weins, Jennifer A. Schaub, Harold Park, Kumar Sharma, M. Todd Valerius, Stephen Daniel, Sean Eddy, Bruce W. Herr, Kenneth W. Dunn, Jamie Snyder, E. Steve Woodle, Dianna Sendrey, Ljiljana Paša-Tolić, Raghavan Murugan, Brandon Ginley, Bryan Kestenbaum, Celia P. Corona-Villalobos, Olivia Balderes, Sushrut Waikar, Carissa Vinovskis, Brooke Berry, Parmjeet Randhawa, Seth Winfree, Jose R. Torrealba, Ning Shang, Rachel Sealfon, Michael J. Ferkowicz, William S. Bush, Jonas Carson, Robert Koewler, Guanshi Zhang, Robert D. Toto, Ian H. de Boer, Gearoid M. McMahon, Andrew N. Hoofnagle, Vijaykumar R. Kakade, Brendon Lutnick, Melissa M. Shaw, Rita R. Alloway, Rajasree Menon, Afolarin Amodu, Jeanine Basta, Paul J. Lee, Ingrid Onul, Sylvia E. Rosas, Cijang (John) He, Andrew S. Bomback, Yinghua Cheng, Jeffrey B. Hodgin, Samir M. Parikh, Garry Nolan, John A. Kellum, Anil Pillai, Annapurna Pamreddy, Orson W. Moe, Jiten Patel, Jonathan J. Taliercio, S. Susan Hedayati, Anitha Vijayan, Tanima Arora, Evren U. Azeloglu, Paul M. Palevsky, Nathan Heath Patterson, Asra Kermani, Becky Steck, Kavya Anjani, Ashley Berglund, Yashvardhan Jain, Stacey E. Jolly, John R. Sedor, George (Holt) Oliver, Natasha Wen, Nancy Wang, Ruikang Wang, Joseph Ardayfio, Michael Rauchman, Ashley R. Burg, Victoria Blanc, Minnie M. Sarwal, Daniel Hall, Sethu M. Madhavan, Sean D. Mooney, Sushrut S. Waikar, Daria Barwinska, Christopher Y. Park, Tara K. Sigdel, Ugochukwu Ugwuowo, John F. O'Toole, Ragnar Palsson, Insa M. Schmidt, Joel M. Henderson, Hongping Ye, Jens Hansen, Jonathan Barasch, Neil Roy, Nicholas Lucarelli, Anna Shpigel, Ashveena Dighe, Elizabeth Record, Sanjay Jain, and Nichole Jefferson

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Urinary system, 030232 urology & nephrology, Kidney, Article, 03 medical and health sciences, 0302 clinical medicine, PEDF, Fibrosis, Biopsy, Humans, Medicine, Osteonectin, Nerve Growth Factors, Prospective Studies, Renal Insufficiency, Chronic, Eye Proteins, Serpins, medicine.diagnostic_test, urogenital system, business.industry, Calcium-Binding Proteins, Cadherins, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Nephrology, Cohort, Disease Progression, Biomarker (medicine), business, Biomarkers, Kidney disease
Abstract

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Published
2021
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50. Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity

Author

Haejin Yoon, Jillian L. Shaw, Anna Greka, and Marcia C. Haigis

Subjects
Computational biology, Biology, Article, Metabolomics, Metabolic Diseases, Lipidomics, Animals, Homeostasis, Humans, Disease, Molecular Biology, Catabolism, Microbiota, Immunity, Lipid metabolism, Cell Biology, Lipid Metabolism, Lipids, Chromatin, Lipotoxicity, Health, lipids (amino acids, peptides, and proteins), Signal transduction, Energy Metabolism, Functional genomics, Function (biology), Signal Transduction
Abstract

Summary Lipids play crucial roles in signal transduction, contribute to the structural integrity of cellular membranes, and regulate energy metabolism. Questions remain as to which lipid species maintain metabolic homeostasis and which disrupt essential cellular functions, leading to metabolic disorders. Here, we discuss recent advances in understanding lipid metabolism with a focus on catabolism, synthesis, and signaling. Technical advances, including functional genomics, metabolomics, lipidomics, lipid-protein interaction maps, and advances in mass spectrometry, have uncovered new ways to prioritize molecular mechanisms mediating lipid function. By reviewing what is known about the distinct effects of specific lipid species in physiological pathways, we provide a framework for understanding newly identified targets regulating lipid homeostasis with implications for ameliorating metabolic diseases.

Published
2021
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