180 results on '"Okusa, Mark D."'
Search Results
2. Bone marrow stromal cell antigen-1 deficiency protects from acute kidney injury.
- Author
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Tsuyoshi Inoue, Ryusuke Umene, Sung, Sun-Sang J., Shinji Tanaka, Liping Huang, Junlan Yao, Noritatsu Hashimoto, Chia-Hsien Wu, Yasuna Nakamura, Tomoya Nishino, Hong Ye, Rosin, Diane L., Katsuhiko Ishihara, and Okusa, Mark D.
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MESENCHYMAL stem cells ,ACUTE kidney failure ,BONE marrow ,RENAL fibrosis ,PARKINSON'S disease - Abstract
This study aimed to investigate the role of bone marrow stromal cell antigen-1 (Bst1; also known as CD157) in acute kidney injury (AKI). Bst1 is a cell surface molecule with various enzymatic activities and downstream intracellular signaling pathways that modulate the immune response. Previous research has linked Bst1 to diseases such as ovarian cancer, Parkinson's disease, and rheumatoid arthritis. We used bilateral ischemia-reperfusion injury (IRI) as an AKI model and created bone marrow chimeric mice to evaluate the role of Bst1 in bone marrow-derived cells. We also used flow cytometry to identify Bst1/CD157 expression in hematopoietic cells and evaluate immune cell dynamics in the kidney. The findings showed that Bst1-deficient (Bst1
-/- ) mice were protected against renal bilateral IRI. Bone marrow chimera experiments revealed that Bst1 expression on hematopoietic cells, but not parenchymal cells, induced renal IRI. Bst1 was mainly found in B cells and neutrophils by flow cytometry of the spleen and bone marrow. In vitro, migration of neutrophils from Bst1-/- mice was suppressed, and adoptive transfer of neutrophils from wild-type Bst1+/+ mice abolished the renal protective effect in Bst1 knockout mice. In conclusion, the study demonstrated that Bst1-/- mice are protected against renal IRI and that Bst1 expression in neutrophils plays a crucial role in inducing renal IRI. These findings suggest that targeting Bst1 in neutrophils could be a potential therapeutic strategy for AKI. NEW & NOTEWORTHY Acute kidney injury (AKI), a serious disease for which there is no effective Federal Drug Administration-approved treatment, is associated with high mortality rates. Bone marrow stromal cell antigen-1 (Bst1) is a cell surface molecule that can cause kidney fibrosis, but its role in AKI is largely unknown. Our study showed that Bst1-/- mice revealed a protective effect against renal bilateral ischemia-reperfusion injury (IRI). Adoptive transfer studies confirmed that Bst1 expression in hematopoietic cells, especially neutrophils, contributed to renal bilateral IRI. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway
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Tanaka, Shinji, Hammond, Benjamin, Rosin, Diane L., and Okusa, Mark D.
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- 2019
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4. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane
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Kenwood, Brandon M., Weaver, Janelle L., Bajwa, Amandeep, Poon, Ivan K., Byrne, Frances L., Murrow, Beverley A., Calderone, Joseph A., Huang, Liping, Divakaruni, Ajit S., Tomsig, Jose L., Okabe, Kohki, Lo, Ryan H., Cameron Coleman, G., Columbus, Linda, Yan, Zhen, Saucerman, Jeffrey J., Smith, Jeffrey S., Holmes, Jeffrey W., Lynch, Kevin R., Ravichandran, Kodi S., Uchiyama, Seiichi, Santos, Webster L., Rogers, George W., Okusa, Mark D., Bayliss, Douglas A., and Hoehn, Kyle L.
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- 2014
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5. IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury
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Stremska, Marta E., Jose, Sheethal, Sabapathy, Vikram, Huang, Liping, Bajwa, Amandeep, Kinsey, Gilbert R., Sharma, Poonam R., Mohammad, Saleh, Rosin, Diane L., Okusa, Mark D., and Sharma, Rahul
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- 2017
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6. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through [α7nAChR.sup.+] splenocytes
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Inoue, Tsuyoshi, Abe, Chikara, Sung, Sun-sang J., Moscalu, Stefan, Jankowski, Jakub, Huang, Liping, Ye, Hong, Rosin, Diane L., Guyenet, Patrice G., and Okusa, Mark D.
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Inflammation -- Analysis ,Reperfusion injury -- Care and treatment ,Vagus nerve stimulation -- Research ,Health care industry - Abstract
The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes., Introduction Acute kidney injury (AKI) is associated with high mortality and morbidity, has an expanding incidence, and is a strong risk factor for chronic kidney disease (CKD) and end stage [...]
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- 2016
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7. Development of a photoacoustic microscopy technique to assess peritubular capillary function and oxygen metabolism in the mouse kidney
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Sun, Naidi, Zheng, Shuqiu, Rosin, Diane L., Poudel, Nabin, Yao, Junlan, Perry, Heather M., Cao, Rui, Okusa, Mark D., and Hu, Song
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- 2021
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8. The 12th consensus conference of the Acute Dialysis Quality Initiative (ADQI XII)†
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Kellum, J. A., Mythen, M. G., Shaw, A. D., Shaw, Andrew D, Kellum, John A, Chawla, Lakhmir S., Chappell, Daniel, Raghunathan, Karthik, Murray, Patrick T., Beattie, W. Scott, Lobo, Dileep N., Myburgh, John, Sladen, Robert, Hoste, Eric A., Maitland, Kathryn, Brudney, Charles S., Mehta, Ravindra, Vincent, Jean-Louis, de Bruxelles, Libre, Yates, David, Goldstein, Stuart L., Bagshaw, Sean M., Cecconi, Maurizio, Okusa, Mark D., Wang, Henry E., Mitchell, H, Ostermann, Marlies, Murugan, Raghavan, Prowle, John R., and Ronco, Claudio
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- 2014
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9. Dendritic cells tolerized with adenosine [A.sub.2A]R agonist attenuate acute kidney injury
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Li, Li, Huang, Liping, Ye, Hong, Song, Steven P., Bajwa, Amandeep, Lee, Sang Ju, Moser, Emily K., Jaworska, Katarzyna, Kinsey, Gilbert R., Day, Yuan J., Linden, Joel, Lobo, Peter I., Rosin, Diane L., and Okusa, Mark D.
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Adenosine -- Properties ,Acute renal failure -- Genetic aspects -- Drug therapy ,Interleukin-10 -- Dosage and administration ,Dendritic cells -- Genetic aspects ,Health care industry - Abstract
DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important anti-inflammatory molecule in tissue inflammation, and adenosine 2A receptor [(A.sub.2A]R) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with [A.sub.2A]R-deficient DCs are more susceptible to kidney IRI and are not protected from injury by [A.sub.2A]R agonists. In addition, administration of DCs treated ex vivo with an [A.sub.2A]R agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A.sub.2A]R agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo [A.sub.2A]R-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI., Introduction Kidney DCs, residing in the interstitial extracellular compartment, are professional APCs and play a critical role in initiating an early immune response against pathogens as well as maintain-ing immunological [...]
- Published
- 2012
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10. IL-17 produced by neutrophils regulates IFN-γ--mediated neutrophil migration in mouse kidney ischemia-reperfusion injury
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Li, Li, Huang, Liping, Vergis, Amy L., Ye, Hong, Bajwa, Amandeep, Narayan, Vivek, Strieter, Robert M., Rosin, Diane L., and Okusa, Mark D.
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Cell migration -- Research -- Health aspects ,Reperfusion injury -- Development and progression -- Care and treatment -- Research ,Neutrophils -- Properties -- Health aspects -- Research ,Biological control systems -- Research -- Health aspects ,Interleukins -- Health aspects -- Research ,Health care industry - Abstract
The IL-23/IL-17 and IL-12/IFN-γ cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-γ signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by [GR-1.sup.+] neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-γ pathway and NKT cells by administering α-galactosylceramide-primed bone marrow-derived DCs increased IFN-γ production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-γ production in either [Il17a.sup.[-/-]] or [Il17r.sup.[-/-]] mice, which suggested that IL-17 signaling was proximal to IFN-γ signaling. This was confirmed by the finding that IFN-γ administration reversed the protection seen in [Il17a.sup.[-/-]] mice subjected to IRI, whereas IL-17A failed to reverse protection in [Ifng.sup.[-/-]] mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-γ and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-γ. These mechanisms might contribute to reperfusion injury in other organs., Introduction The heterodimeric cytokines IL-12 and IL-23, which are secreted mainly by activated DCs and macrophages in response to TLR activation (1), (2), stimulate T cell differentiation and function in [...]
- Published
- 2010
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11. Complement factor H gene associations with end-stage kidney disease in African Americans
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Bonomo, Jason A., Palmer, Nicholette D., Hicks, Pamela J., Lea, Janice P., Okusa, Mark D., Langefeld, Carl D., Bowden, Donald W., and Freedman, Barry I.
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- 2014
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12. A basic science view of acute kidney injury biomarkers
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Charlton, Jennifer R., Portilla, Didier, and Okusa, Mark D.
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- 2014
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13. Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury
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Sharma, Ashish K., LaPar, Damien J., Zhao, Yunge, Li, Li, Lau, Christine L., Kron, Irving L., Iwakura, Yoichiro, Okusa, Mark D., and Laubach, Victor E.
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- 2011
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14. Dangers Within: DAMP Responses to Damage and Cell Death in Kidney Disease
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Rosin, Diane L. and Okusa, Mark D.
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- 2011
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15. Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes
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Awad, Alaa S., Rouse, Michael, Liu, Lixia, Vergis, Amy L., Rosin, Diane L., Linden, Joel, Sedor, John R., and Okusa, Mark D.
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- 2008
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16. Role of Natural IgM and IgM induced Bregs in preventing ischemia induced innate inflammation and AKI
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Lobo, Peter I. and Okusa, Mark D.
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Inflammation ,B-Lymphocytes, Regulatory ,Immunoglobulin M ,Ischemia ,Animals ,Humans ,Acute Kidney Injury ,urologic and male genital diseases ,Kidney ,Article ,Immunity, Innate ,Autoantibodies - Abstract
Ischemic acute kidney injury (AKI) is predominantly mediated by the innate inflammatory response to damage-associated molecular patterns released during the reperfusion phase of the ischemic event. In this study, we show that pre-emptive IgM infusions to increase binding of natural IgM (nIgM) anti-leucocyte autoantibodies (IgM-ALA), inhibit this inflammatory response and prevent AKI in mice. Similarly, AKI was prevented by pre-emptively infusing Bregs, induced ex vivo by pre-treating pan-B cells with nIgM. Harnessing such a physiologic mechanism to inhibit inflammation and prevent ischemia-induced AKI can have translational potential in humans. For example, one can pre-emptively infuse IgM or ex vivo induced Bregs in patients who have a high risk of developing ischemia-induced AKI, especially the subset of these patients with low levels of IgM-ALA or regulatory T cells (Tregs).
- Published
- 2019
17. T cells and T-cell receptors in acute renal failure
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Portilla, Didier and Okusa, Mark D
- Published
- 2006
18. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells
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Day, Yuan-Ji, Huang, Liping, McDuffie, Marcia J., Rosin, Diane L., Ye, Hong, Chen, Jiang-Fan, Schwarzschild, Michael A., Fink, J. Stephen, Linden, Joel, and Okusa, Mark D.
- Published
- 2003
19. Enhanced protection from renal ischemia: Reperfusion injury with A2A-adenosine receptor activation and PDE 4 inhibition
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Okusa, Mark D., Linden, Joel, Huang, Liping, Rosin, Diane L., Smith, David F., and Sullivan, Gail
- Published
- 2001
20. Expression of Acsm2, a kidney-specific gene, parallels the function and maturation of proximal tubular cells.
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Hirofumi Watanabe, Paxton, Robert L., Tolerico, Matthew R., Nagalakshmi, Vidya K., Shinji Tanaka, Okusa, Mark D., Shin Goto, Ichiei Narita, Seiji Watanabe, Sequeira-Lpez, Maria Luisa S., and Gomez, R. Ariel
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KIDNEY development ,CHRONIC kidney failure ,ACUTE kidney failure ,NEPHROLOGY ,DNA data banks ,URETERIC obstruction ,EPIGENOMICS - Abstract
The acyl-CoA synthetase medium-chain family member 2 (Acsm2) gene was first identified and cloned by our group as a kidney-specific "KS" gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the Acsm2 gene was expressed specifically and at a high level in normal adult kidneys. Expression of Acsm2 in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that Acsm2 was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the Acsm2 gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of Acsm2 in the proximal tubules was significantly decreased. In human samples, the expression pattern of ACSM2A, a homolog of mouse Acsm2, was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of Acsm2 parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that Acms2 may serve as a novel marker of proximal tubular injury and/or dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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21. Nonpharmacological – biomechanical approaches to control inflammation in AKI
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Tanaka, Shinji, Inoue, Tsuyoshi, Hossack, John, and Okusa, Mark D.
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Inflammation ,Stress, Physiological ,Animals ,Humans ,Acute Kidney Injury ,Article ,Biomechanical Phenomena - Abstract
Inflammation is broadly recognized as an important factor in the pathogenesis of acute kidney injury, but pharmacological approaches to alleviate inflammation in acute kidney injury have been without success in clinical trials. Neuromodulation by non-pharmacological methods is emerging as a novel therapeutic strategy against inflammatory diseases. Recently, our group and others have demonstrated that vagus nerve stimulation and pulsed ultrasound ameliorated inflammation via the cholinergic anti-inflammatory pathway in various animal models, including renal ischemia-reperfusion injury. Delineating the precise mechanisms by which these methods activate the cholinergic anti-inflammatory pathway and ameliorate inflammation is mandatory for the broad clinical application in the future. Novel techniques, such as optogenetics, are expected to elucidate these complex mechanisms.
- Published
- 2017
22. Ultrasound for the treatment of acute kidney injury and other inflammatory conditions: a promising path toward noninvasive neuroimmune regulation.
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Jieru Cai, Nash, William T., and Okusa, Mark D.
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Acute kidney injury (AKI) is an important clinical disorder with high prevalence, serious consequences, and limited therapeutic options. Modulation of neuroimmune interaction by non-pharmacological methods is emerging as a novel strategy for treating inflammatory diseases, including AKI. Recently, pulsed ultrasound (US) treatment was shown to protect from AKI by stimulating the cholinergic anti-inflammatory pathway. Because of the relatively simple, portable, and noninvasive nature of US procedures, US stimulation may be a valuable therapeutic option for treating inflammatory conditions. This review discusses potential impacts of US bioeffects on the nervous system and how this may generate feedback onto the immune system. We also discuss recent evidence supporting the use of US as a means to treat AKI and other inflammatory diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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23. Kidney Mentoring and Assessment Program for Students: a guide for engaging medical students in nephrology.
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Bayliss, George P, Cobb, Jason, Decker, Brian, Hellman, Richard, Vasavada, Nina, Mackelaite, Lina, Shadur, Craig, Ilori, Titilayo, Ibrahim, Tod, Leight, Katlyn, Hsiao, Li-Li, Molitoris, Bruce A, Okusa, Mark D, Parker, Mark G, and Committee, ASN Workforce
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MEDICAL students ,MENTORING ,KIDNEYS ,MEDICAL schools ,COMMUNITY organization - Abstract
Background The American Society of Nephrology's (ASN) Workforce Committee created a unique program called the Kidney Mentoring and Awareness Program for Students to engage medical students in the fight against kidney diseases and interest them in careers in nephrology. Methods The program provided a framework and 2 years of funding to three medical schools to organize and carry out health screenings in underserved areas of their communities as well as a structure for student mentoring by the practicing nephrologists. Results The Workforce Committee identified three medical schools (Emory University, Atlanta, GA; Indiana University, Indianapolis, IN and University of Louisville, Louisville, KY) and engaged faculty at each school to serve as advisors. The ASN committed funding to the groups for 2 years, after which the groups became self-sufficient. Three nephrologists participated in each chapter, building on existing relationships with community groups to identify sites and carry out kidney screening events. Conclusions We report here the experience of those chapters and a blueprint for other schools interested in setting up a similarly structured program to interest students in nephrology while working with community groups to spread awareness of the major underlying causes of kidney disease. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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24. Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment.
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Perry, Heather M., Görldt, Nicole, Sung, Sun-sang J., Liping Huang, Rudnicka, Kinga P., Encarnacion, Iain M., Bajwa, Amandeep, Tanaka, Shinji, Poudel, Nabin, Junlan Yao, Rosin, Diane L., Schrader, Jürgen, and Okusa, Mark D.
- Abstract
—Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5'-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1
+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor- immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73-/- kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2019
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25. Natural IgM switches the function of LPS activated murine bone marrow dendritic cells (BMDC) to a 'regulatory' DC that suppresses innate inflammation1
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Lobo, Peter I, Schlegel, Kailo H., Bajwa, Amandeep, Huang, Liping, Kurmaeva, Elvira, Wang, Binru, Ye, Hong, Tedder, Thomas F., Kinsey, Gilbert R., and Okusa, Mark D.
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Inflammation ,Lipopolysaccharides ,Mice, Knockout ,B-Lymphocytes ,Mice, Inbred BALB C ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,Transcription Factor RelA ,Bone Marrow Cells ,Dendritic Cells ,Kidney ,Lymphocyte Activation ,Article ,Interleukin-10 ,Mice, Inbred C57BL ,Mice ,Immunoglobulin M ,Reperfusion Injury ,Animals ,CD40 Antigens ,Phosphorylation ,Cells, Cultured ,Signal Transduction - Abstract
We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.5 × 10(6) IgM/LPS-pretreated BMDC, when injected into wild-type C57BL/6 mice 24 h before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS-activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require IL-10 and programmed death 1 as well as downregulation of CD40 and p65 NF-κB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/LPS-pretreated BMDC or using IL-10 knockout BMDC fails to induce protection. Similarly, IgM/LPS-pretreated BMDC are rendered nonprotective by increasing CD40 expression and phosphorylation of p65 NF-κB. How IgM/LPS regulatory BMDC suppress in vivo ischemia-induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, CD25(+) T cells, B cells, IL-10, and circulating IgM. There was no increase in Foxp3(+) regulatory T cells in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leukocyte Abs can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation.
- Published
- 2015
26. Metabolic Syndrome Severity and Risk of CKD and Worsened GFR: The Jackson Heart Study.
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DeBoer, Mark D., Filipp, Stephanie L., Musani, Solomon K., Sims, Mario, Okusa, Mark D., and Gurka, Matthew
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CHRONIC kidney failure ,GLOMERULAR filtration rate ,KIDNEY diseases ,KIDNEY function tests ,ALBUMINS ,PATIENTS - Abstract
The metabolic syndrome (MetS), as assessed using dichotomous criteria, is associated with increased risk of future chronic kidney disease (CKD), though this relationship is unclear among African Americans, who have lower risk for MetS but higher risk for CKD.Background/Aims: We performed logistic regression using a sex- and race-specific MetS-severity z-score to assess risk of incident CKD among 2,627 African-American participants of the Jackson Heart Study, assessed at baseline and 8 years later. Based on quartile of baseline MetS severity, we further assessed prevalence of being in the lowest quartile of baseline GFR, the lowest quartile of relative GFR at follow-up, microalbuminuria and incident CKD.Methods: Higher MetS-severity was associated with higher prevalence of GFR in the lowest quartile at baseline among males and females. Among African-American females but not males, higher baseline MetS-severity was associated with a higher prevalence of baseline elevations in microabuminuria (p<0.01), steep decline in GFR (p<0.001) and a higher incidence of CKD (p<0.0001). Women in increasing quartiles of baseline MetS-severity exhibited a linear trend toward higher odds of future CKD (p<0.05), with those in the 4Results: th quartile of MetS-severity (compared to the 1st ) having an odds ratio of 2.47 (95% confidence interval 1.13, 5.37); no such relationship was seen among men (p value for trend 0.49). MetS-severity exhibited sex-based interactions regarding risk for future GFR deterioration and CKD, with increasing risk in women but not men. These data may have implications for triggering CKD screening among African-American women with higher degrees of MetS-severity. [ABSTRACT FROM AUTHOR]Conclusion: - Published
- 2018
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27. Natural IgM and TLR Agonists Switch Murine Splenic Pan-B to "Regulatory" Cells That Suppress Ischemia-Induced Innate Inflammation via Regulating NKT-1 Cells.
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Lobo, Peter I., Schlegel, Kailo H., Bajwa, Amandeep, Liping Huang, and Okusa, Mark D.
- Subjects
LEUCOCYTES ,BONE marrow ,KIDNEY injuries - Abstract
Natural IgM anti-leukocyte autoantibodies (IgM-ALAs) inhibit inflammation by several mechanisms. Here, we show that pan-B cells and bone marrow-derived dendritic cells (BMDCs) are switched to regulatory cells when pretreated ex vivo with IgM. B cells are also switched to regulatory cells when pretreated ex vivo with CpG but not with LPS. Pre-emptive infusion of such ex vivo induced regulatory cells protects C57BL/6 mice from ischemia-induced acute kidney injury (AKI) via regulation of in vivo NKT-1 cells, which normally amplify the innate inflammatory response to DAMPS released after reperfusion of the ischemic kidney. Such ex vivo induced regulatory pan-B cells and BMDC express low CD1d and inhibit inflammation by regulating in vivo NKT-1 in the context of lowlipid antigen presentation and by a mechanism that requires costimulatory molecules, CD1d, PDL1/PD1, and IL10. Second, LPS and CpG have opposite effects on induction of regulatory activity in BMDC and B cells. LPS enhances regulatory activity of IgMpretreated BMDC but negates the IgM-induced regulatory activity in B cells, while CpG, with or without IgM pretreatment, induces regulatory activity in B cells but not in BMDC. Differences in the response of pan-B and dendritic cells to LPS and CpG, especially in the presence of IgM-ALA, may have relevance during infections and inflammatory disorders where there is an increased IgM-ALA and release of TLRs 4 and 9 ligands. Ex vivo induced regulatory pan-B cells could have therapeutic relevance as these easily available cells can be pre-emptively infused to prevent AKI that can occur during open heart surgery or in transplant recipients receiving deceased donor organs. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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28. Neuroimmune Interactions in Inflammation and Acute Kidney Injury.
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Inoue, Tsuyoshi, Tanaka, Shinji, and Okusa, Mark D.
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INFLAMMATION ,KIDNEY diseases ,VAGUS nerve - Abstract
Inflammation contributes to the pathogenesis of a wide variety of disorders including kidney diseases. Recent advances have shown that neural pathways are able to regulate immunity and inflammation. The cholinergic anti-inflammatory pathway (CAP) is a well-studied neural circuit involving the vagus nerve that is thought to contribute to the response to inflammatory disorders. Expression of receptors for neurotransmitters is found in some immune cells, including β2 adrenergic receptors on CD4 T cells and alpha 7 subunit of the nicotinic acetylcholine (ACh) receptor on macrophages. Once nerves are activated, neurotransmitters such as norepinephrine and ACh are released at nerve terminals, and the neurotransmitters can activate immune cells located in close proximity to the nerve terminals. Thus, vagus nerve stimulation induces activation of immune cells, leading to an anti-inflammatory response. Recent studies demonstrate a non-pharmacological organ protective effect of electrical nerve stimulation, pulsed ultrasound treatment, or optogenetic C1 neuron activation. These modalities are thought to activate the CAP and attenuate inflammation. In this review, we will focus on the current understanding of the mechanisms regarding neuroimmune interactions with a particular focus on inflammation associated with kidney disease. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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29. Reading between the (guide)lines--the KDIGO practice guideline on acute kidney injury in the individual patient.
- Author
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Okusa, Mark D and Davenport, Andrew
- Abstract
The KDIGO guidelines for acute kidney injury (AKI) are designed to assist health-care providers around the world in managing patients with AKI. Clinical guidelines are intended to help the clinician make an informed decision based on review of the currently available evidence. Due to the generic nature of guidelines, it is sometimes difficult to translate a guideline for a particular individual patient who may have specific clinical circumstances. To illustrate this point, we have discussed the interpretation of the KDIGO guideline in patients who have subtleties in their clinical presentation, which may make treatment decisions less than straightforward. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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30. Role of leukocytes in the pathogenesis of acute kidney injury.
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Kinsey, Gilbert R. and Okusa, Mark D.
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ACUTE kidney failure ,LEUCOCYTES ,IMMUNE response ,MOLECULAR immunology ,IMMUNOLOGY of inflammation ,MACROPHAGE activation ,NEUTROPHIL immunology ,DENDRITIC cells ,CATASTROPHIC illness ,IMMUNITY - Abstract
The article discusses the role of the immune system in the pathogenesis of acute kidney injury (AKI), specifically white blood cells, or leucocytes. Topics include the immune response in AKI, studies showing various innate immune cells promote renal injury, such as neutrophils, macrophages, and natural killer (NK) cells, and an in-depth discussion on the detrimental role of several pro-inflammatory leucocytes, including neutrophils, macrophages, and dendritic cells.
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- 2012
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31. Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury.
- Author
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Awad, Alaa S., Kinsey, Gilbert R., Khutsishvili, Konstantine, Gao, Ting, Bolton, W. Kline, and Okusa, Mark D.
- Subjects
MONOCYTES ,MACROPHAGES ,CHEMOKINES ,PEOPLE with diabetes ,KIDNEY diseases ,BLOOD sugar ,LABORATORY mice - Abstract
Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN). C-C chemokine receptor (CCR)2 regulates monocyte/macrophage migration into injured tissues. However, the direct role of CCR2-mediated monocyte/macrophage recruitment in diabetic kidney disease remains unclear. We report that pharmacological blockade or genetic deficiency of CCR2 confers kidney protection in Ins2
Akita and streptozotocin (STZ)-induced diabetic kidney disease. Blocking CCR2 using the selective CCR2 antagonist RS504393 for 12 wk in Ins2Akita mice significantly attenuated albuminuria, the increase in blood urea nitrogen and plasma creatinine, histological changes, and glomerular macrophage recruitment compared with vehicle. Furthermore, mice lacking CCR2 (CCR2-/- ) mimicked CCR2 blockade by reducing albuminuria and displaying less fibronectin mRNA expression and inflammatory cytokine production compared with CCR2+/+ mice, despite comparable blood glucose levels. Bone marrow-derived monocytes from CCR2+/+ or CCR2-/- mice adoptively transferred into CCR2-/- mice reversed the renal tissue-protective effect in diabetic CCR2-/- mice as evaluated by increased urinary albumin excretion and kidney macrophage recruitment, indicating that CCR2 is not required for monocyte migration from the circulation into diabetic kidneys. These findings provide evidence that CCR2 is necessary for monocyte/macrophage-induced diabetic renal injury and suggest that blocking CCR2 could be a novel therapeutic approach in the treatment of DN. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
32. Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.
- Author
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Awad, Alaa S., Hong Ye, Liping Huang, Li Li, Foss Jr., Frank W., Macdonald, Timothy L., Lynch, Kevin R., and Okusa, Mark D.
- Subjects
SPHINGOSINE ,CELLULAR mechanics ,ISCHEMIA ,REPERFUSION injury ,KIDNEY diseases ,ETHANOLAMINES ,BIOGENIC amines - Abstract
The mechanisms involved in renal ischemia-reperfusion injury (IRI) are complex and appear to involve the early participation of bone marrow-derived cells. T lymphocytes participate in the pathogenesis of IRI. Sphingosine 1-phosphate (S1P) induces peripheral T cell depletion. Therefore, we hypothesized that S1P
1 receptor activation protects kidney from IRI. FTY-720, a non-receptor-selective sphingosine analog, was given intraperitoneally to C57BL/6 mice, and animals were subjected to ischemia for 32 min followed by reperfusion for 24 h. Plasma creatinine, blood count, myeloperoxidase (MPO) activity, and renal histology were determined. IRI led to a marked increase in plasma creatinine, MPO activity, leukocyte infiltration, and vascular permeability. FTY-720 significantly decreased plasma creatinine in a dose-response manner with a maximal reduction of ∼73 and ∼69% with doses of 240 and 48 μg/kg, respectively. MPO, leukocyte infiltration, vascular permeability, and peripheral blood lymphocyte counts were markedly decreased with FTY-720 treatment. The protective effect of FTY-720 was reversed with VPC-44116, a selective S1P1 receptor antagonist. Furthermore, SEW-2871, a selective S1P1 agonist, significantly decreased plasma creatinine in a dose-response manner with a maximal reduction of ∼70% with a dose of 10 mg/kg. Analysis of kidneys by light microscopy revealed minimal histological signs of ischemic injury with FTY-720 or SEW-2871 treatment compared with the vehicle group. Using RT-PCR, we found a time-dependent increase in the S1P1 mRNA expression following IRI that begins after 2 h with the maximum expression at ∼4 h. We conclude that the protective effect of FTY-720 is due primarily to activation of S1P1 receptors. The mechanism of protection is not known but may be related to peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P1 receptor. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
33. Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy.
- Author
-
Awad, Alaa S., Liping Huang, Hong Ye, Thu Anh Duong, Elizabeth, Bolton, W. Kline, Linden, Joel, and Okusa, Mark D.
- Subjects
ADENOSINES ,DIABETIC nephropathies ,INFLAMMATION ,KIDNEY diseases ,TISSUES ,ALBUMINS ,EXCRETION - Abstract
We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A
2A -receptor (A2A R) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A2A R agonists in a chronic model of renal injury. We hypothesized that A2A agonists mediate renal tissue protection in diabetic nephropathy by reducing glomerular inflammation. Diabetes was induced with single intravenous injection of streptozotocin in Sprague-Dawley rats (50 mg/kg). Increases in urinary albumin excretion (UAE) and plasma creatinine at week 6 in the diabetes group (26- and 6-fold over control, respectively) were markedly reduced by continuous subcutaneous administration of ATL146e (10 ng·kg-1 ·min-1 ), a selective A2A agonist. The increase in UAE in the diabetes group was associated with a significant reduction in the expression of slit diaphragm-associated molecules compared with control (nephrin; P < 0.05 and podocin; P < 0.005) that was reversed by ATL146e treatment. Diabetes led to an increase in urinary excretion of monocyte chemoattractant protein-1 (705% of control), TNF-α (1,586% of control), IFN-γ (298% of control), kidney fibronectin mRNA (457% of control), and glomerular infiltration of macrophages (764% of control), effects significantly reduced by ATL146e treatment. Mesangial expansion and basement membrane thickness were reduced with ATL146e. To further confirm the selectivity of ATL146e, we used wild-type (WT) or A2A knockout (A2A -KO) mice. Four weeks after diabetes, UAE increased significantly in both WT and A2A -KO diabetic mice (3.0- and 3.3-fold over control). A2A agonist treatment blocked the increase in UAE in WT diabetic mice (P < 0.001), whereas it had no effect on the A2A -KO diabetic mice. These results demonstrate that chronic A2A R activation in diabetic rats 1) ameliorates histological and functional changes in kidneys induced by diabetes and 2) causes reduced inflammation associated with diabetic nephropathy. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
34. Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF.
- Author
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Shenyang Li, Gokden, Neriman, Okusa, Mark D., Bhatt, Renu, and Portilla, Didier
- Subjects
ACUTE kidney failure ,KIDNEY diseases ,PEROXISOMES ,CISPLATIN ,OXIDATION ,APOPTOSIS ,NECROSIS ,KIDNEY tubules - Abstract
Recently, we demonstrated that peroxisome proliferator-activated receptor-α (PPARα) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990–F998, 2004). In the following studies, we examined the protective effect of PPARα ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-α, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARα ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARα ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARα null mice. In addition, we observed that cisplatin-induced NF-κB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARα ligand. These results demonstrate that PPARα exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-κB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
35. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages.
- Author
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Yuan-Ji Day, Liping Huang, Hong Ye, Linden, Joel, and Okusa, Mark D.
- Subjects
REPERFUSION injury ,ISCHEMIA ,BLOOD circulation disorders ,KIDNEY injuries ,MACROPHAGES ,PHAGOCYTES ,ACUTE kidney failure ,SMALL interfering RNA - Abstract
The role of monocytes/macrophages in the pathogenesis of ischemia-reperfusion injury ORB is unknown. We sought to determine whether activation of macrophage adenosine 2A (A
2A ) receptors (A2A Rs) mediates tissue protection We subjected C57B1/6 mice infused with clodronate [dichloromethylene bisphosphonate (Cl2 MBP)] to IRI (32 min of ischemia followed by 24 h of reperfusion) to deplete them of macrophages. IRI induced an elevation of plasma creatinine that was reduced with Cl2 MBP (26% of control). Adoptive transfer of murine RAW 264.7 cells reconstituted injury, an effect blocked significantly by A2A agonists (27% of plasma creatinine from mice reconstituted with macrophages). Macrophages subjected to A2A knockout by small interfering RNA were adoptively transferred to macrophage-depleted mice and reconstituted injury (110% of control mice); however, the increase in plasma creatinine was blocked by A2A agonists (20% of vehicle treatment). Finally, the A2A agonist effect on IRI was blocked in macrophage-depleted A2A -knockout mice reconstituted with wild-type RAW 264.7 cells. RNase protection assays 24 h after IRI demonstrated that macrophages are required for IL-6 and TGF-β mRNA induction. However, A2A agonist-mediated tissue protection is independent of IL-6 and TGF-β mRNA. We conclude that the full extent of IRI requires macrophages and that A2A agonist-mediated tissue protection is independent of activation of macrophage A2A Rs. [ABSTRACT FROM AUTHOR]- Published
- 2005
- Full Text
- View/download PDF
36. Protection from ischemic liver injury by activation of A[sub 2A] adenosine receptors during reperfusion: inhibition of chemokine induction.
- Author
-
Yuan-Ji Day, Marshall, Melissa A., Liping Huang, McDuffie, Marcia J., Okusa, Mark D., and Linden, Joel
- Subjects
CELL receptors ,ADENOSINES ,LIVER ,ISCHEMIA ,REPERFUSION ,CHEMOKINES - Abstract
Investigates the effect of A[sub 2A] adenosine receptors (A[sub 2A]AR) activation on protection of the liver from ischemia-reperfusion (I/R) injury and determines whether suppression of hepatic inflammatory chemokine production plays a role in this protection. Demonstration that the selective agonist of the A[sub 2a]AR produces a protection of wild-type C57BL/6 mice from liver I/R injury that is absent in congenic animals lacking the A[sub 2A]AR gene.
- Published
- 2004
- Full Text
- View/download PDF
37. Selective blockade of lysophosphatidic acid LPA[sub 3] receptors reduces murine renal ischemia-reperfusion injury.
- Author
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Okusa, Mark D., Hong Ye, Liping Huang, Sigismund, Laura, Macdonald, Timothy, and Lynch, Kevi R.
- Subjects
- *
LYSOPHOSPHOLIPIDS , *ACUTE kidney failure , *REPERFUSION injury , *G proteins - Abstract
Lysophosphatidic acid (LPA) released during ischemia has diverse physiological effects via its G protein-coupled receptors, LPA[sub 1], LPA[sub 2], and LPA[sub 3] (formerly Edg-2, -4, and -7). We tested the hypothesis that selective blockade of LPA receptors affords protection from renal ischemia-reperfusion (UR) injury. By real-time PCR, LPA[sub 1-3] receptor mRNAs were expressed in mouse renal cortex, outer medulla, and inner medulla with the following rank order LPA[sub 3] = LPA[sub 2] > LPA[sub 1]. In C57BL/6 mice whose kidneys were subjected to ischemia and reperfusion, treatment with a selective LPA3 agonist, oleoyl-methoxy phosphothionate (OMPT), enhanced injury. In contrast, a dual LPA[sub 1]/LPA[sub 3]-receptor antagonist, VPC-12249, reduced UR injury, but this protective effect was lost when the antagonist was coadministered with OMPT. Interestingly, delaying administration of VPC-12249 until 30 min after the start of reperfusion did not alter its efficacy significantly. We conclude that VPC-12249 reduces renal I/R injury predominantly by LPA3 receptor blockade and could serve as a novel compound in the treatment ofischemia acute renal failure. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
38. A[sub 2A] adenosine receptor: a novel therapeutic target in renal disease.
- Author
-
Okusa, Mark D.
- Subjects
- *
ADENOSINES , *KIDNEY diseases - Abstract
Focuses on the characteristics of the A[sub 2A] adenosine receptor and its potential in treating and preventing renal diseases. Pharmacology and molecular biology of receptors; Localization and functional effects of receptors in kidney; Comparative affinities of A[sub 2A] ligands for human adenosine receptor subtypes and signaling elements.
- Published
- 2002
- Full Text
- View/download PDF
39. Enhanced protection from renal ischemia: Reperfusion injury with A2A -adenosine receptor activation and PDE 4 inhibition.
- Author
-
Okusa, Mark D., Linden, Joel, Huang, Liping, Rosin, Diane L., Smith, David F., and Sullivan, Gail
- Subjects
- *
ISCHEMIA , *REPERFUSION injury , *PHOSPHODIESTERASES , *CHEMICAL inhibitors - Abstract
Enhanced protection from renal ischemia: Reperfusion injury with A2A -adenosine receptor activation and PDE 4 inhibition. Background. We previously demonstrated in rats and mice that agonists of A2A -adenosine receptors (A2A -ARs) reduce renal injury following ischemia-reperfusion. We now extend these studies and examine the effects of ATL-146e (formerly DWH-146e), an A2A -AR agonist, and rolipram, a type IV phosphodiesterase (PDE 4) inhibitor, on murine renal injury following ischemia-reperfusion. Methods. C57BL/6 mice were treated with rolipram, ATL-146e, or both compounds combined and were subjected to renal ischemia for 32 minutes and reperfusion for 24 to 48 hours. In vitro studies were performed on suspended and adhering human neutrophils. Results. Continuous delivery of rolipram or ATL-146e during reperfusion reduced renal injury in a dose-dependent manner. Maximal protection was observed when ATL-146e was infused for six hours during reperfusion. Elevated plasma creatinine and myeloperoxidase activity produced by ischemia-reperfusion were reduced by rolipram (0.1 ng/kg/min) and ATL-146e (10 ng/kg/min) by up to approximately 60% and 70%, respectively. Co-infusion of both compounds produced a maximum reduction of plasma creatinine of approximately 90% and myeloperoxidase activity. In vitro studies on suspended and adhering human neutrophils demonstrated that selective stimulation of A2A -ARs by ATL-146e increased cAMP accumulation, reduced oxidative activity of activated neutrophils, and decreased activated neutrophil adherence. These responses were potentiated by rolipram. Conclusions. We conclude that the combined infusion of ATL-146e and rolipram leads to enhanced renal tissue protection from ischemia-reperfusion by mechanisms that may include reduced neutrophil adherence/recruitment and release of reactive oxygen species. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
40. A[sub 2A] adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion.
- Author
-
Okusa, Mark D. and Linden, Joel
- Subjects
- *
ADENOSINES , *KIDNEY diseases , *PATHOLOGICAL physiology , *PHYSIOLOGY - Abstract
Discusses a study which determined the mechanisms responsible for the reduced renal tissue injury by agonists of adenosine receptors. Methods; Results; Discussion.
- Published
- 2000
- Full Text
- View/download PDF
41. Selective A... adenosine receptor activation reduces ischemia-reperfusion injury in rat kidney.
- Author
-
Okusa, Mark D. and Linden, Joel
- Subjects
- *
ADENOSINES , *REPERFUSION injury , *LABORATORY rats , *ISCHEMIA , *PATHOLOGICAL physiology , *PHYSIOLOGY , *ANIMAL models in research - Abstract
Presents information on a study which examined the effect of selective activation of A... adenosine receptors on ischemia-reperfusion injury in rat kidney. Methods of the study; Results and discussion.
- Published
- 1999
- Full Text
- View/download PDF
42. Regulation of adenylyl cyclase in polarized renal epithelial cells by G protein-coupled receptors.
- Author
-
Okusa, Mark D. and Liping Huang
- Subjects
- *
POLARIZATION (Nuclear physics) , *ADENYLATE cyclase , *ADENOSINES - Abstract
Examine the influence of polarization of receptor expression on the activity of adenylyl cyclase. Alpha2B-adenosine receptor expression at the basolateral domain of LLC-PK1 cells; Effects of alpha2B-adrenergic receptor expression on cAMP accumulation in the LLC-PK1 cells; Polarized renal epithelial cell membrane characterized by domains differing functionally.
- Published
- 1997
- Full Text
- View/download PDF
43. Distant organ injury following acute kidney injury.
- Author
-
Awad, Alaa S. and Okusa, Mark D.
- Subjects
- *
KIDNEY diseases , *ORGANS (Anatomy) - Abstract
The article discusses an article on distant organ injury following acute kidney injury published within the issue including one by Hassoun and colleagues and another by Hoke and others.
- Published
- 2007
- Full Text
- View/download PDF
44. Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation.
- Author
-
Morioka, Sho, Kajioka, Daiki, Yamaoka, Yusuke, Ellison, Rochelle M., Tufan, Turan, Werkman, Inge L., Tanaka, Shinji, Barron, Brady, Ito, Satoshi T., Kucenas, Sarah, Okusa, Mark D., and Ravichandran, Kodi S.
- Subjects
- *
PROTEIN folding , *PHOSPHATIDYLSERINES , *PROTEOLYSIS , *REPERFUSION injury , *CHIMERIC proteins , *INFLAMMATION - Abstract
Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis , denoted "chimeric receptor for efferocytosis" (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation. [Display omitted] Design of chimeric receptors for efferocytosis (CHEF) to enhance efferocytosis Boosting efferocytosis via CHEF attenuates multiple inflammatory insults in vivo Protein folding and misfolded protein degradation are rate-limiting steps in efferocytosis CHEF expression can improve outcomes in ongoing disease Chimeric receptors comprising an extracellular phosphatidylserine recognition domain and the signalling domain of a cytoplasmic adaptor protein boost clearance of apoptotic cells in damaged tissue and improve the disease outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
45. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes.
- Author
-
Tsuyoshi Inoue, Chikara Abe, Sung, Sun-sang J., Moscalu, Stefan, Jankowski, Jakub, Liping Huang, Hong Ye, Rosin, Diane L., Guyenet, Patrice G., and Okusa, Mark D.
- Subjects
- *
VAGUS nerve , *NEURAL stimulation , *REPERFUSION injury , *INFLAMMATION , *NICOTINIC acetylcholine receptors - Abstract
The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
46. Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference.
- Author
-
Murray, Patrick T, Mehta, Ravindra L, Shaw, Andrew, Ronco, Claudio, Endre, Zoltan, Kellum, John A, Chawla, Lakhmir S, Cruz, Dinna, Ince, Can, and Okusa, Mark D
- Subjects
- *
BIOMARKERS , *KIDNEY injuries , *KIDNEY diseases , *CLINICAL trials , *CLINICAL medicine - Abstract
Over the last decade there has been considerable progress in the discovery and development of biomarkers of kidney disease, and several have now been evaluated in different clinical settings. Although there is a growing literature on the performance of various biomarkers in clinical studies, there is limited information on how these biomarkers would be utilized by clinicians to manage patients with acute kidney injury (AKI). Recognizing this gap in knowledge, we convened the 10th Acute Dialysis Quality Initiative meeting to review the literature on biomarkers in AKI and their application in clinical practice. We asked an international group of experts to assess four broad areas for biomarker utilization for AKI: risk assessment, diagnosis, and staging; differential diagnosis; prognosis and management; and novel physiological techniques including imaging. This article provides a summary of the key findings and recommendations of the group, to equip clinicians to effectively use biomarkers in AKI. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
47. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury.
- Author
-
Li Li, Liping Huang, Hong Ye, Song, Steven P., Bajwa, Amandeep, Sang Ju Lee, Moser, Emily K., Jaworska, Katarzyna, Kinsey, Gilbert R., Day, Yuan J., Linden, Joel, Lobo, Peter I., Rosin, Diane L., and Okusa, Mark D.
- Subjects
- *
DENDRITIC cells , *ADENOSINES , *ACUTE kidney failure , *KILLER cells , *IMMUNE response , *ANTI-inflammatory agents , *LEUCOCYTES - Abstract
DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/ reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important anti-inflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
48. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes.
- Author
-
Awad, Alaa S., Rouse, Michael D., Khutsishvili, Konstantine, Liping Huang, Bolton, W. Kline, Lynch, Kevin R., and Okusa, Mark D.
- Subjects
- *
KIDNEY diseases , *DIABETES , *ETHANOLAMINES , *DIABETIC nephropathies , *TUMOR necrosis factors , *ANTINEOPLASTIC antibiotics - Abstract
Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
49. Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney.
- Author
-
Kinsey, Gilbert R., Huang, Liping, Vergis, Amy L., Li Li, and Okusa, Mark D.
- Subjects
- *
REPERFUSION , *T cells , *ACUTE kidney failure , *ISCHEMIA , *INFLAMMATION - Abstract
Reperfusion following ischemia is associated with acute kidney injury and inflammation. Using a mouse model, we exposed the kidney to a nonlethal period of ischemia, rendering it refractory to future ischemia-induced dysfunction. This ischemic preconditioning is partially mediated by Treg lymphocytes that suppress immune responses. We found that this maneuver significantly inhibited the accumulation of neutrophils and macrophages, tubular necrosis, and loss of kidney function caused by a subsequent ischemia/reperfusion injury 1 week later. The initial ischemia/reperfusion caused a significant increase in CD4+CD25+FoxP3+ and CD4+CD25+IL-10+ Treg cells within the kidney at 7 days of reperfusion. Treatment of preconditioned mice with a Treg cell–depleting antibody (PC61) reversed the effect of preconditioning on kidney neutrophil accumulation and partially inhibited the functional and histological protection of preconditioning. Adoptive transfer of Treg cells in naive mice, before ischemia/reperfusion, mimicked the protective and anti-inflammatory effects of ischemic preconditioning on the kidney. These studies highlight the role of Treg cells in ischemic preconditioning. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
50. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury.
- Author
-
Awad, Alaa S, Rouse, Michael, Liping Huang, Vergis, Amy L, Reutershan, Jörg, Cathro, Helen P, Linden, Joel, and Okusa, Mark D
- Subjects
- *
KIDNEY injuries , *NEUTROPHILS , *ISCHEMIA , *BLOOD circulation disorders , *CARDIOPULMONARY system , *VASCULAR endothelium - Abstract
During renal ischemia-reperfusion, local and distant tissue injury is caused by an influx of neutrophils into the affected tissues. Here we measured the kinetics of margination and transmigration of neutrophils in vivo in the kidney and lungs following renal ischemia-reperfusion. After bilateral renal injury, kidney neutrophil content increased threefold at 24 h. The neutrophils were found primarily in the interstitium and to a lesser degree marginated to the vascular endothelium. These interstitial neutrophils had significantly lower levels of intracellular IFN-γ, IL-4, IL-6, and IL-10 a tendency for decreased amounts of IL-4 and TNF-α compared to the marginated neutrophils. Localization of the neutrophils to the kidney interstitium was confirmed by high resolution microscopy and these sites of transmigration were directly associated with areas of increased vascular permeability. Activation of the adenosine 2A receptor significantly decreased both kidney neutrophil transmigration by about half and vascular permeability by about a third. After unilateral renal ischemia-reperfusion, the unclipped kidney and lungs did not accumulate interstitial neutrophils or have increased vascular permeability despite a marked increase of neutrophil margination in the lungs. Our findings suggest there is a sequential recruitment and transmigration of neutrophils from the vasculature into the kidney interstitium at the site of tissue injury following renal ischemia-reperfusion.Kidney International (2009) 75, 689–698; doi:10.1038/ki.2008.648; published online 7 January 2009 [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
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