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1. Intracellular calcium release modulates polycystin-2 trafficking

Author

Miyakawa Ayako, Ibarra Cristián, Malmersjö Seth, Aperia Anita, Wiklund Peter, and Uhlén Per

Subjects
Polycystin-2, Protein trafficking, Calcium signaling, Kidney cells, Autosomal dominant polycystic kidney disease, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Polycystin-2 (PC2), encoded by the gene that is mutated in autosomal dominant polycystic kidney disease (ADPKD), functions as a calcium (Ca2+) permeable ion channel. Considerable controversy remains regarding the subcellular localization and signaling function of PC2 in kidney cells. Methods We investigated the subcellular PC2 localization by immunocytochemistry and confocal microscopy in primary cultures of human and rat proximal tubule cells after stimulating cytosolic Ca2+ signaling. Plasma membrane (PM) Ca2+ permeability was evaluated by Fura-2 manganese quenching using time-lapse fluorescence microscopy. Results We demonstrated that PC2 exhibits a dynamic subcellular localization pattern. In unstimulated human or rat proximal tubule cells, PC2 exhibited a cytosolic/reticular distribution. Treatments with agents that in various ways affect the Ca2+ signaling machinery, those being ATP, bradykinin, ionomycin, CPA or thapsigargin, resulted in increased PC2 immunostaining in the PM. Exposing cells to the steroid hormone ouabain, known to trigger Ca2+ oscillations in kidney cells, caused increased PC2 in the PM and increased PM Ca2+ permeability. Intracellular Ca2+ buffering with BAPTA, inositol 1,4,5-trisphosphate receptor (InsP3R) inhibition with 2-aminoethoxydiphenyl borate (2-APB) or Ca2+/Calmodulin-dependent kinase inhibition with KN-93 completely abolished ouabain-stimulated PC2 translocation to the PM. Conclusions These novel findings demonstrate intracellular Ca2+-dependent PC2 trafficking in human and rat kidney cells, which may provide new insight into cyst formations in ADPKD.

Published
2013
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2. Spatial distribution of Na+-K+-ATPase in dendritic spines dissected by nanoscale superresolution STED microscopy

Author

Bondar Alexander, Widengren Jerker, Spicarova Zuzana, Scott Lena, Rönnlund Daniel, Blom Hans, Aperia Anita, and Brismar Hjalmar

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background The Na+,K+-ATPase plays an important role for ion homeostasis in virtually all mammalian cells, including neurons. Despite this, there is as yet little known about the isoform specific distribution in neurons. Results With help of superresolving stimulated emission depletion microscopy the spatial distribution of Na+,K+-ATPase in dendritic spines of cultured striatum neurons have been dissected. The found compartmentalized distribution provides a strong evidence for the confinement of neuronal Na+,K+-ATPase (α3 isoform) in the postsynaptic region of the spine. Conclusions A compartmentalized distribution may have implications for the generation of local sodium gradients within the spine and for the structural and functional interaction between the sodium pump and other synaptic proteins. Superresolution microscopy has thus opened up a new perspective to elucidate the nature of the physiological function, regulation and signaling role of Na+,K+-ATPase from its topological distribution in dendritic spines.

Published
2011
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6. Nanoscale elucidation of Na,K-ATPase isoforms in dendritic spines

Author

Liebmann, Thomas, Blom, Hans, Aperia, Anita, and Brismar, Hjalmar

Subjects
Physics - Biological Physics, Quantitative Biology - Neurons and Cognition, Quantitative Biology - Subcellular Processes
Abstract

The dimensions of neuronal synapses suggest that optical super-resolution imaging methods are necessary for thorough investigation of protein distributions and interactions. Nanoscopic evaluation of neuronal samples has presented practical hurdles, but advancing methods are making synaptic protein topology and quantification measurements feasible. This work explores the application of Photoactivated Localization Microscopy (PALM) pointilistic super-resolution imaging for investigation of the membrane bound sodium pump, the Na,K-ATPase, in matured neurons. Two isoforms of the sodium pump (ATP1a1 and ATP1a3) were studied in cultured neurons using the PALM-compatible fluorescent proteins PAGFP and mEos. Nanoscopic imaging reveals a compartmentalized distribution of sodium pumps in dendritic spines. Several nanoclusters of pumps are typically found in the spine head and relatively few in the spine neck. The density of sodium pumps was estimated from a quantification of detected single molecules to 600-800 pump copies/um2 in the spine heads. We have utilized PALM for dissection of nanoscale localization in mature cultured neurons and demonstrated similar topology and quantification estimates with PAGFP and mEos. PALM topology assessments of the sodium pump appeared similar to previous STED studies, though quantification estimates varied notably, implying that sample labeling strategies and choice of nanoscopic imaging method are critical factors for correct quantification.

Published
2013

14. AT1-receptor response to non-saturating Ang-II concentrations is amplified by calcium channel blockers

Author

Kristoffer Bernhem, Kalaiselvan Krishnan, Alexander Bondar, Hjalmar Brismar, Anita Aperia, and Lena Scott

Subjects
Calcium, AT1R, Cell imaging, VGCC, hypertension, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Blockers of angiotensin II type 1 receptor (AT1R) and the voltage gated calcium channel 1.2 (CaV1.2) are commonly used for treatment of hypertension. Yet there is little information about the effect of physiological concentrations of angiotensin II (AngII) on AT1R signaling and whether there is a reciprocal regulation of AT1R signaling by CaV1.2. Methods To elucidate these questions, we have studied the Ca2+ signaling response to physiological and pharmacological AngII doses in HEK293a cells, vascular smooth muscle cells and cardiomyocytes using a Ca2+ sensitive dye as the principal sensor. Intra-cellular calcium recordings were performed in presence and absence of CaV1.2 blockers. Semi-quantitative imaging methods were used to assess the plasma membrane expression of AT1R and G-protein activation. Results Repeated exposure to pharmacological (100 nM) concentrations of AngII caused, as expected, a down-regulation of the Ca2+ response. In contrast, repeated exposure to physiological (1 nM) AngII concentration resulted in an enhancement of the Ca2+ response. The up-regulation of the Ca2+ response to repeated 1 nM AngII doses and the down-regulation of the Ca2+ response to repeated 100 nM Angll doses were not accompanied by a parallel change of the AT1R plasma membrane expression. The Ca2+ response to 1 nM of AngII was amplified in the presence of therapeutic concentrations of the CaV1.2 blockers, nifedipine and verapamil, in vascular smooth muscle cells, cardiomyocytes and HEK293a cells. Amplification of the AT1R response was also observed following inhibition of the calcium permeable transient receptor potential cation channels, suggesting that the activity of AT1R is sensitive to calcium influx. Conclusions Our findings have implications for the understanding of hyperactivity of the angiotensin system and for use of Ca2+ channel blockers as mono-therapy in hypertension.

Published
2017
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17. Socio-demographic Characteristics, Sexual and Test-Seeking Behaviours Amongst Men Who have Sex with Both Men and Women: Results from a Bio-behavioural Survey in 13 European Cities

Author

Mirandola, Massimo, Gios, Lorenzo, Sherriff, Nigel, Pachankis, John, Toskin, Igor, Ferrer, Laia, Dias, Sónia, Velicko, Inga, Staneková, Danica, Caplinskas, Saulius, Naseva, Emilia, Niedźwiedzka-Stadnik, Marta, Mirandola, Massimo, Gios, Lorenzo, Benvenuti, Stefano, Davis, Ruth Joanna, Lunardi, Massimo, Menichelli, Silvana, Breveglieri, Michele, Vanden Berghe, Wim, de Groot, Peter, Nöstlinger, Christiana, van Wijk, Veronica, Fransen, Katrien, Vermoesen, Tine, Vanackere, Michiel, Benchikha, Fourat, van den Eynde, Sandra, Cruyssaert, Boris, Sergeant, Mark, Blondeel, Karel, Damen, Pieter, Massoz, François, Carlier, Erwin, François, Michael, Karon, Stephen, Soltani, Safia, Martin, Thierry, De Bruyne, Alan, Bocken, Françoise, Dieleman, Myriam, Alexiev, Ivailo, Dimitrova, Reneta, Gancheva, Anna, Bogeva, Dobromira, Nikolova, Maria, Muhtarova, Mariya, Kantarjiev, Todor, Georgieva, Viara, Naseva, Emilia, Tsintsarski, Petar, Taskov, Hristo, Varleva, Tonka, Birindjieva, Elena, Angelova, Aneliya, Antonov, Manol, Marcus, Ulrich, Schink, Susanne Barbara, Dudareva-Vizule, Sandra, an der Heiden, Matthias, Marzougui, Sami, Bremer, Viviane, Kühne, Andrea, Schönerstedt-Zastrau, Kerstin, Zimmermann, Ruth, Wille, Andreas, Eckstein, Kai, Buch, Norman, Moskophidis, Philipp, Grenz, Marc, Schmogro, Danilo, Cornaglia, Giuseppe, Zorzi, Antonella, Tonolli, Elisabetta, Lo Cascio, Giuliana, Todeschini, Teresa, Recchia, Manuela, Pattini, Lorella, Rocca, Maria, Bighignoli, Alessandra, Galardi, Anita, Martini, Loredana, Cobello, Francesco, Bovo, Chiara, Bortolami, Oscar, Crestani, Laura, Comperini, Fabiano, Concia, Ercole, Lattuada, Emanuela, Lanzafame, Massimiliano, Del Bravo, Paola, Cordioli, Maddalena, Rigo, Fabio, Guardalben, Emanuele, Marchesoni, Ivan, Suligoi, Barbara, Regine, Vincenza, Pugliese, Lucia, Caplinskas, Saulius, Caplinskiene, Irma, Krupenkaite, Rima, Sargelis, Gediminas, Rudomanskis, Arturas, Dias, Sónia, Gama, Ana, Brás, Oriana, Piedade, João, Fuertes, Ricardo, Pinto, Nuno, Brito, João, Esteves, Júlio, Rojas, Jesus, Ferreira, Fernando, Rocha, Miguel, Machado, Hugo, Campos, Maria José, Mendão, Luís, Rosińska, Magdalena, Kucharczyk, Bożena, Niedźwiedzka-Stadnik, Marta, Henszel, Łukasz, Zieliński, Andrzej, Czerwiński, Michał, Pawlęga, Michał, Burdon, Ewelina, Gajdemska, Małgorzata, Guściora, Agnieszka, Klasik, Nikodem, Rżanek, Katarzyna, Sawicki, Michał, Tęcza, Michał, Dębski, Mateusz, Maciejewska, Anna, Pazdan, Izabela, Rafila, Alexandru, Pitigoi, Daniela, Abagiu, Adrian, Marin, Carolina, Panzariu, Ioana, Miroiu, Alexandru, Popa, Madalina, Likker, Monica, Georgescu, Maria, Musat, Galina, Cojocaru, Dan, Lixandru, Mihai, Teodorescu, Raluca, Staneková, Danica, Hábeková, Monika, Drobková, Tatiana, Chabadová, Zuzana, Wimmerova, Soňa, Mojzesová, Maria, Kunč, Filip, Skurák, Michal, Bodnar, Peter, Horniaková, Katarína, Krahulcová, Mária, Präsensová, Jarmila, Smoleň, Martin, Záhradník, Peter, Tibaj, Pavol, Klavs, Irena, Kustec, Tanja, Adamič, Claudia, Poljak, Mario, Krošelj, Robert, Mlakar, Jana, Šolinc, Miran, Folch, Cinta, Ferrer, Laia, Montoliu, Alexandra, Casabona, Jordi, Esteve, Anna, Galdon, Montserrat, Gonzalez, Victoria, Muñoz, Rafael, Axelsson, Maria, Berglund, Torsten, Kuhlmann-Berenzon, Sharon, Tsoumanis, Achilleas, Velicko, Inga, Janson, Christer, Lindh, Bartek, Aperia, Kajsa, Babulanam, Buddha, Carlberg, Hans, Davidsson, Malte, Entenza Gutierrez, Nedo, Hildingsson, Viktor, Klasson, Henrik, Peña Ramos, Moises, Quintero Rojas, Cristian, Sandberg, Sven-Olof, Samuelson, Andreas, Sjöberg, Eric, Sjölund, Tommy, Svensson, Simon, Valencia, Iván, Garcia, Filip, Lindblad, Olov, Voss, Jon, Ask, Ronnie, Blaxhult, Anders, Maliniemi, Maarit, Ideström, Monica, Blom, Nils, Sherriff, Nigel, Panton, Christina, Flood, Glynis, Fransen, Katrien, Vermoesen, Tine, Boseley, Ross, Tweed, Marc, Roberts, Jonathon, Menel Lemos, Cinthia, Guglielmetti, Paolo, Philipp, Wolfgang, Amato, Andrew, Dinca, Irina, Haar, Karin, Pharris, Anastasia, Noori, Teymur, Toskin, Igor, Maurer, Natalie, Zohrabyan, Lev, Iovita, Alexandrina, Campioni, Maddalena, Noack, Patrick, Peeling, Rosanna, Johnston, Lisa, and the Sialon II Network

Published
2017
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24. ”Vi har väldigt mycket grejer här, men det är alla olika känslor” : En undersökning om bakgrundsmusik i bildsalen

Author

Aperia, Emilie and Aperia, Emilie

Abstract

Denna studie undersöker fenomenet bakgrundsmusik i bildklassrum och hur elever upplever att detta inverkar för möjligheterna att arbeta med sitt skapande. Detta görs då fenomenet är vanligt förekommande. Min studie utgick från en fenomenologisk ansats för att få syn på hur elever upplever ett fenomen. Teoretiskt är studien inspirerad av Biestas syn på eleversmöjligheter att handla och vara subjekt. Studiens syfte är undersöka och få syn på hur elever upplever att musik i bildsalen inverkar för deras möjlighet att arbeta med sitt skapande samtbidra med nyanseringar av hur vi kan förhålla oss till fenomenet. Frågor som ställs i studien ärföljande:På vilka sätt inverkar musik i bildsalen för elevers möjligheter att arbeta med sitt skapande?Utifrån denna fråga utvecklades följande frågor:På vilka sätt uttrycker elever att olika musikgenrer som spelas inverkar?Har sättet musik blir tillgänglig för elever inverkan för upplevd delaktighet på bildlektionen och varför? Undersökningen gjordes i en årskurs 9 och metoder för empiriinsamling var deltagande observation, bildelicitering och fältanteckningar. Empirin analyseras med följande teorier och begrepp: subjekt, att stå i dialog, grit och groove. I studiens resultatdel besvaras frågeställningarna. I slutdiskussionen lyfter jag frågor att undersöka vidare. Mitt gestaltande arbete bestod av en workshop på Konstfacks vårutställning. Deltagarna fick utföra enfärgblandningsuppgift samtidigt som olika musik spelade. Vi diskuterade deltagarnas reflektioner om hur de upplevde att olika musik inverkade när de skapade.

Published
2022

25. 'We have very many things here, but it's like all the different emotions.' : A study about background music in the art classroom

Author

Aperia, Emilie

Subjects
musik, Pedagogy, groove, subjekt, Pedagogik, stå i dialog, grit
Abstract

Denna studie undersöker fenomenet bakgrundsmusik i bildklassrum och hur elever upplever att detta inverkar för möjligheterna att arbeta med sitt skapande. Detta görs då fenomenet är vanligt förekommande. Min studie utgick från en fenomenologisk ansats för att få syn på hur elever upplever ett fenomen. Teoretiskt är studien inspirerad av Biestas syn på eleversmöjligheter att handla och vara subjekt. Studiens syfte är undersöka och få syn på hur elever upplever att musik i bildsalen inverkar för deras möjlighet att arbeta med sitt skapande samtbidra med nyanseringar av hur vi kan förhålla oss till fenomenet. Frågor som ställs i studien ärföljande:På vilka sätt inverkar musik i bildsalen för elevers möjligheter att arbeta med sitt skapande?Utifrån denna fråga utvecklades följande frågor:På vilka sätt uttrycker elever att olika musikgenrer som spelas inverkar?Har sättet musik blir tillgänglig för elever inverkan för upplevd delaktighet på bildlektionen och varför? Undersökningen gjordes i en årskurs 9 och metoder för empiriinsamling var deltagande observation, bildelicitering och fältanteckningar. Empirin analyseras med följande teorier och begrepp: subjekt, att stå i dialog, grit och groove. I studiens resultatdel besvaras frågeställningarna. I slutdiskussionen lyfter jag frågor att undersöka vidare. Mitt gestaltande arbete bestod av en workshop på Konstfacks vårutställning. Deltagarna fick utföra enfärgblandningsuppgift samtidigt som olika musik spelade. Vi diskuterade deltagarnas reflektioner om hur de upplevde att olika musik inverkade när de skapade.

Published
2022

29. An interaction between PRRT2 and Na+/K+ ATPase contributes to the control of neuronal excitability

Author

Anna Corradi, Michele Oneto, Flavia Valtorta, Alessandra Romei, Pietro Baldelli, Chiara Parodi, Fabio Benfenati, Davide Aprile, Bruno Sterlini, Anna Fassio, Pierluigi Valente, Anita Aperia, Sterlini, Bruno, Romei, Alessandra, Parodi, Chiara, Aprile, Davide, Oneto, Michele, Aperia, Anita, Valente, Pierluigi, Valtorta, Flavia, Fassio, Anna, Baldelli, Pietro, Benfenati, Fabio, and Corradi, Anna

Subjects
Proteomics, Cellular neuroscience, Molecular neuroscience, Paediatric neurological disorders, Proteomics, Cancer Research, ATPase, Immunology, Nerve Tissue Proteins, Molecular neuroscience, Synaptic Transmission, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Cellular neuroscience, Humans, Na+/K+-ATPase, lcsh:QH573-671, Neurotransmitter, Adenosine Triphosphatases, Neurons, biology, Chemistry, lcsh:Cytology, Colocalization, Membrane Proteins, Afterhyperpolarization, Cell Biology, respiratory system, Cell biology, Paediatric neurological disorders, biology.protein, PRRT2
Abstract

Mutations in PRoline Rich Transmembrane protein 2 (PRRT2) cause pleiotropic syndromes including benign infantile epilepsy, paroxysmal kinesigenic dyskinesia, episodic ataxia, that share the paroxysmal character of the clinical manifestations. PRRT2 is a neuronal protein that plays multiple roles in the regulation of neuronal development, excitability, and neurotransmitter release. To better understand the physiopathology of these clinical phenotypes, we investigated PRRT2 interactome in mouse brain by a pulldown-based proteomic approach and identified α1 and α3 Na+/K+ ATPase (NKA) pumps as major PRRT2-binding proteins. We confirmed PRRT2 and NKA interaction by biochemical approaches and showed their colocalization at neuronal plasma membrane. The acute or constitutive inactivation of PRRT2 had a functional impact on NKA. While PRRT2-deficiency did not modify NKA expression and surface exposure, it caused an increased clustering of α3-NKA on the plasma membrane. Electrophysiological recordings showed that PRRT2-deficiency in primary neurons impaired NKA function during neuronal stimulation without affecting pump activity under resting conditions. Both phenotypes were fully normalized by re-expression of PRRT2 in PRRT2-deficient neurons. In addition, the NKA-dependent afterhyperpolarization that follows high-frequency firing was also reduced in PRRT2-silenced neurons. Taken together, these results demonstrate that PRRT2 is a physiological modulator of NKA function and suggest that an impaired NKA activity contributes to the hyperexcitability phenotype caused by PRRT2 deficiency.

Published
2021

32. Ouabain‐regulated phosphoproteome reveals molecular mechanisms for Na + , K + ‐ATPase control of cell adhesion, proliferation, and survival

Author

Elena Panizza, Jacopo M. Fontana, Hjalmar Brismar, Kozo Hamada, Katsuhiko Mikoshiba, Janne Lehtiö, Evgeny E. Akkuratov, Liang Zhang, Lena Scott, Daniel Svensson, and Anita Aperia

Subjects
Models, Molecular, 0301 basic medicine, Proteome, Protein Conformation, Apoptosis, Biochemistry, Ouabain, Kidney Tubules, Proximal, 0302 clinical medicine, Chlorocebus aethiops, Inositol 1,4,5-Trisphosphate Receptors, calcium and calmodulin–dependent protein kinase, Protein phosphorylation, Phosphorylation, RNA, Small Interfering, inositol triphosphate receptor, CAMK, Chemistry, Kinase, phosphoproteomics, Cell biology, COS Cells, RNA Interference, Mitogen-Activated Protein Kinases, Sodium-Potassium-Exchanging ATPase, Cell Division, Biotechnology, medicine.drug, kidney, Cell Survival, Down-Regulation, 03 medical and health sciences, Cell Adhesion, Genetics, medicine, Animals, Amino Acid Sequence, Calcium Signaling, Na+/K+-ATPase, Cell adhesion, Molecular Biology, Research, Inositol trisphosphate receptor, Rats, Glucose, 030104 developmental biology, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Protein Kinases, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

The ion pump Na+, K+–ATPase (NKA) is a receptor for the cardiotonic steroid ouabain. Subsaturating concentration of ouabain triggers intracellular calcium oscillations, stimulates cell proliferation and adhesion, and protects from apoptosis. However, it is controversial whether ouabain-bound NKA is considered a signal transducer. To address this question, we performed a global analysis of protein phosphorylation in COS-7 cells, identifying 2580 regulated phosphorylation events on 1242 proteins upon 10- and 20-min treatment with ouabain. Regulated phosphorylated proteins include the inositol triphosphate receptor and stromal interaction molecule, which are essential for initiating calcium oscillations. Hierarchical clustering revealed that ouabain triggers a structured phosphorylation response that occurs in a well-defined, time-dependent manner and affects specific cellular processes, including cell proliferation and cell-cell junctions. We additionally identify regulation of the phosphorylation of several calcium and calmodulin–dependent protein kinases (CAMKs), including 2 sites of CAMK type II-γ (CAMK2G), a protein known to regulate apoptosis. To verify the significance of this result, CAMK2G was knocked down in primary kidney cells. CAMK2G knockdown impaired ouabain-dependent protection from apoptosis upon treatment with high glucose or serum deprivation. In conclusion, we establish NKA as the coordinator of a broad, tightly regulated phosphorylation response in cells and define CAMK2G as a downstream effector of NKA.—Panizza, E., Zhang, L., Fontana, J. M., Hamada, K., Svensson, D., Akkuratov, E. E., Scott, L., Mikoshiba, K., Brismar, H., Lehtiö, J., Aperia, A. Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+–ATPase control of cell adhesion, proliferation, and survival.

Published
2019
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39. Super-resolution microscopy reveals that Na+/K+-ATPase signaling protects against glucose-induced apoptosis by deactivating Bad

Author

Kristoffer Bernhem, Anita Aperia, Lena Scott, Jacopo M. Fontana, Linnéa Nilsson, Daniel Svensson, Hjalmar Brismar, Liang Zhang, and Hans Blom

Subjects
0301 basic medicine, Male, Cancer Research, Time Factors, Immunology, bcl-X Protein, Apoptosis, Pharmacology, Mitochondrion, Kidney, Models, Biological, Ouabain, Article, Rats, Sprague-Dawley, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cytosol, medicine, Animals, Na+/K+-ATPase, Super-resolution microscopy, Protein kinase B, bcl-2-Associated X Protein, Microscopy, QH573-671, Chemistry, Kinase, Transporter, Epithelial Cells, Cell Biology, Ligand (biochemistry), Mitochondria, 030104 developmental biology, Glucose, Cytoprotection, Calcium-Calmodulin-Dependent Protein Kinases, bcl-Associated Death Protein, Sodium-Potassium-Exchanging ATPase, Cytology, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, medicine.drug, Protein Binding, Signal Transduction
Abstract

Activation of the apoptotic pathway is a major cause of progressive loss of function in chronic diseases such as neurodegenerative and diabetic kidney diseases. There is an unmet need for an anti-apoptotic drug that acts in the early stage of the apoptotic process. The multifunctional protein Na+,K+-ATPase has, in addition to its role as a transporter, a signaling function that is activated by its ligand, the cardiotonic steroid ouabain. Several lines of evidence suggest that sub-saturating concentrations of ouabain protect against apoptosis of renal epithelial cells, a common complication and major cause of death in diabetic patients. Here, we induced apoptosis in primary rat renal epithelial cells by exposing them to an elevated glucose concentration (20 mM) and visualized the early steps in the apoptotic process using super-resolution microscopy. Treatment with 10 nM ouabain interfered with the onset of the apoptotic process by inhibiting the activation of the BH3-only protein Bad and its translocation to mitochondria. This occurred before the pro-apoptotic protein Bax had been recruited to mitochondria. Two ouabain regulated and Akt activating Ca2+/calmodulin-dependent kinases were found to play an essential role in the ouabain anti-apoptotic effect. Our results set the stage for further exploration of ouabain as an anti-apoptotic drug in diabetic kidney disease as well as in other chronic diseases associated with excessive apoptosis.

Published
2021

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