Classical studies have revealed a central role for the Renin-Angiotensin system (RAS) in the emergence and progression of proteinuria and chronic kidney disease. Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are to date the treatment of choice for the delay of disease progression. Podocyte dysfunction, represented by proteinuria, foot process effacement (FPE) and disruption of the slit diaphragm (SD), is often the initial insult leading to progressive kidney disease. The identification of human mutations in the Ca2+-permeable ion channel TRPC6 as a cause of inherited Focal Segmental Glomerulosclerosis (FSGS) brought Ca2+ biology to the forefront of podocyte research. Our recently published work revealed that both TRPC5 and TRPC6 are important Ca2+ influx pathways in podocytes. The Renin-Angiotensin system (RAS) and RAS/Ca2+ signaling is critical for the structural and functional integrity of podocytes. Podocyte-specific transgenic overexpression of the Angiotensin II type 1 receptor (AT1R) in rats (AT1R Tg) results in podocyte hypertrophy, proteinuria, and ultimately FSGS, but the molecular mechanisms leading to disease are not well understood. Work in the PI's laboratory provided a mechanistic link between AT1R activation and subsequent Ca2+ influx in podocytes through TRPC5 and TRPC6 channels. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocyte migration. TRPC5-mediated degradation of synaptopodin and loss of stress fibers can be rescued by CsA, placing TRPC5 upstream of calcineurin-mediated signaling in podocytes. Here we propose to test our hypothesis that AT1R-mediated activation of TRPC5 causes CsA-sensitive proteinuria and podocyte hypertrophy. At later stages, upregulation of TRPC6 abundance leads to excess Ca2+ toxicity and podocyte death. This area of research is highly relevant to human disease, because proteinuria and associated kidney disease is a major health-care problem affecting millions of people worldwide, and there are currently no targeted, podocyte-preserving therapies available in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095045-05
Application #
9212128
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2014-03-10
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
5
Fiscal Year
2017
Total Cost
$347,456
Indirect Cost
$151,706
Name
Brigham and Women's Hospital
Department
Type
Independent Hospitals
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Wang, Longfei; Fu, Tian-Min; Zhou, Yiming et al. (2018) Structures and gating mechanism of human TRPM2. Science 362:
Sieber, Jonas; Wieder, Nicolas; Clark, Abbe et al. (2018) GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death. Cell Chem Biol 25:175-184.e4
Buvall, Lisa; Wallentin, Hanna; Sieber, Jonas et al. (2017) Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes. J Am Soc Nephrol 28:837-851
Zhou, Yiming; Castonguay, Philip; Sidhom, Eriene-Heidi et al. (2017) A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358:1332-1336
Gipson, Deb (2016) Clinical Trials in FSGS: Past Challenges and New Trial Designs. Semin Nephrol 36:453-459
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Wieder, Nicolas; Greka, Anna (2016) Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies. Pediatr Nephrol 31:1047-54
Yoon, Kyoung Wan; Byun, Sanguine; Kwon, Eunjeong et al. (2015) Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 349:1261669

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