Progressive proteinuric kidney diseases are on the rise worldwide with more than 500 million people affected, and yet no effective therapies exist to halt their progression to kidney failure. High blood pressure and diabetes remain the biggest drivers of progressive kidney diseases worldwide. One big challenge is that the specific molecules and kidney cells involved in progression of kidney diseases remain poorly understood. Our recent work funded by this grant revealed two such molecules, Rac1 and TRPC5, as responsible for the injury and death of precious kidney cells called podocytes. Loss of podocytes resulted in proteinuria, the hallmark of a broken kidney filter barrier and ultimate kidney failure. Funded by this grant, we also discovered a TRPC5 blocker, called AC1903, which can prevent Rac1-TRPC5 from injuring podocytes. In two rat models of a kidney disease called FSGS (Focal and Segmental Glomerulosclerosis), we showed that AC1903 prevented kidney filter damage and protected podocytes, making this an excellent candidate for the development of a future therapy for patients. However, at this time, it is not clear if AC1903 or other TRPC channel blockers can be helpful in protecting the kidneys of patients with hypertension or diabetes-related kidney diseases. Therefore, the goal of this revised competitive renewal application is to build on our recent discoveries and perform careful and detailed studies in rat and mouse models of progressive kidney diseases to gain further insight into the role of TRPC ion channels and their blockers in the treatment of kidney diseases associated with hypertension and diabetes. This work will pave the way for new therapies for kidney disease patients, which are greatly needed.

Public Health Relevance

The overall goal of this revised competitive renewal application is to build on our recent discoveries on the efficacy of TRPC5 inhibitors in animal models of FSGS to gain further insight into the role of TRPC ion channels and their inhibitors in the treatment of progressive proteinuric kidney diseases associated with hypertension and diabetes, for which there is tremendous unmet clinical need.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK099465-06A1
Application #
9818007
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Maric-Bilkan, Christine
Project Start
2014-09-20
Project End
2023-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Christov, Marta; Clark, Abbe R; Corbin, Braden et al. (2018) Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities. JCI Insight 3:
Trachtman, Howard; Gipson, Debbie S; Somers, Michael et al. (2018) Randomized Clinical Trial Design to Assess Abatacept in Resistant Nephrotic Syndrome. Kidney Int Rep 3:115-121
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
Greka, Anna (2016) Human genetics of nephrotic syndrome and the quest for precision medicine. Curr Opin Nephrol Hypertens 25:138-43
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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