Abstract
Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 1332-1336 |
| Number of pages | 5 |
| Journal | Science |
| Volume | 358 |
| Issue number | 6368 |
| DOIs | |
| State | Published - 8 Dec 2017 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2017, American Association for the Advancement of Science. All rights reserved.
Funding
We thank T. Tickle for guidance on RNA-seq analysis; K. Maeda for technical assistance with the Dahl S rat studies; L. Gaffney for assistance with graphics; and A. Blobaum and X. Zhan for technical assistance with in vivo pharmacokinetics work. This work was funded by NIH grants DK095045, DK099465, DK103658, DK083511, and DK093746 (A.G.); NIH grant U54-MD007598 (J.M.B.); NIH grant DK103658 (C.R.H.); an F31CA195701 fellowship (A.R.C.); a National Defense Science and Engineering Graduate fellowship (E.-H.S.); a Deutsche Forschungs Gesellschaft fellowship WI 4612/1-1 (N.W.); a Broad–Israel Science Foundation Fellowship (M.D.-L.); and a Deutsche Forschungs Gesellshaft Collaborative Research Center 1118 grant (S.C.H.). A.G. has a financial interest in Goldfinch Biopharma, a biotechnology company focused on discovery and development of precision therapies for patients with kidney disease. A.G.’s financial interest in Goldfinch Bio was reviewed and is managed by Brigham and Women’s Hospital–Partners HealthCare and the Broad Institute of MIT and Harvard in accordance with their conflict-of-interest policies. E.S.L. is on the Scientific Advisory Board of Third Rock Ventures (TRV), which is a lead investor in Goldfinch Bio. Under his agreement with TRV, his compensation consists solely of stock in TRV-founded companies. This agreement excludes his receiving stock from certain companies, including Goldfinch Bio. Partners HealthCare–Brigham and Women’s Hospital, the University of Nebraska Medical Center, and the authors (A.G. and C.R.H.) have filed a patent application (no. 62/555,219) covering AC1903. The TRPC5 inhibitor compound AC1903 is available from C.R.H. (the University of Nebraska Medical Center) under a materials transfer agreement. All RNA-seq data files are deposited at GEO (accession no. GSE103020).
| Funders | Funder number |
|---|---|
| Broad–Israel Science Foundation | |
| Deutsche Forschungs Gesellschaft | WI 4612/1-1 |
| Deutsche Forschungs Gesellshaft Collaborative Research Center | |
| National Institutes of Health | DK093746, DK103658, DK083511, DK095045, F31CA195701, U54-MD007598 |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01DK099465 |
| University of Nebraska Medical Center | |
| Massachusetts Institute of Technology | |
| National Defense Science and Engineering Graduate | |
| Deutsche Forschungsgemeinschaft | |
| Israel Science Foundation |