A NOX4/TRPC6 pathway in podocyte calcium pegulation and renal damage in diabetic kidney disease
| العنوان: | A NOX4/TRPC6 pathway in podocyte calcium pegulation and renal damage in diabetic kidney disease |
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| المؤلفون: | Kristen Winsor, Aron M. Geurts, Allen W. Cowley, Gregory Blass, Lutz Birnbaumer, Vladislav Levchenko, Daria V. Ilatovskaya, Alexander Staruschenko, Tengis S. Pavlov, Leonid S. Shuyskiy, Oleg Palygin, Michael Grzybowski |
| المصدر: | Journal of the American Society of Nephrology. 2018;29(7):1917-1927 Repositorio Institucional (UCA) Pontificia Universidad Católica Argentina instacron:UCA |
| بيانات النشر: | American Society of Nephrology, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, GENES, chemistry.chemical_element, 030204 cardiovascular system & hematology, Calcium, medicine.disease_cause, Diabetes Mellitus, Experimental, Podocyte, Diabetic nephropathy, Mice, 03 medical and health sciences, ENFERMEDADES RENALES, 0302 clinical medicine, Internal medicine, Calcium flux, TRPC6 Cation Channel, medicine, Animals, Diabetic Nephropathies, NEFROLOGIA, TRPC Cation Channels, Mice, Knockout, Calcium metabolism, Rats, Inbred Dahl, urogenital system, Podocytes, PROTEINAS, Angiotensin II, Calcium channel, RIÑON, CALCIO, NOX4, Hydrogen Peroxide, General Medicine, medicine.disease, Rats, Basic Research, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, NADPH Oxidase 4, Nephrology, Reactive Oxygen Species, Oxidative stress |
| الوصف: | Fil: Ilatovskaya, Daria V. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Blass, Gregory. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Palygin, Oleg. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Levchenko, Vladislav. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Pavlov, Tengis S. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Grzybowski, Michael N. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Winsor, Kristen. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Shuyskiy, Leonid S. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Geurts, Aron M. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Cowley, Allen W. Medical College of Wisconsin. Department of Physiology; Estados Unidos Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Staruschenko, Alexander. Medical College of Wisconsin. Department of Physiology; Estados Unidos Abstract: Background: Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly H2O2, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived H2O2 contributes to podocyte damage in DKD via elevation of podocyte calcium.Methods We used Dahl salt-sensitive (SS) rats with a null mutation for the Nox4 gene (SSNox4-/-) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli.Results Upon induction of type 1 diabetes with streptozotocin, SSNox4-/- rats exhibited significantly lower basal intracellular Ca2+ levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II-elicited calcium flux was blunted in glomeruli isolated from diabetic SSNox4-/- rats compared with that in glomeruli from diabetic SS rats. H2O2 stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from Trpc6-knockout mice and, in a similar manner, in podocytes from Trpc5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from Trpc6-knockout or Trpc5/6 double-knockout mice were protected from damage induced by H2O2 to the same extent.Conclusions These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a6765873d03d43ec7fd5240e4a59d65aTest https://repositorio.uca.edu.ar/handle/123456789/8693Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a6765873d03d43ec7fd5240e4a59d65a |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |