A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models
Gaining a foothold on kidney disease? The leading cause of kidney disease worldwide is known as focal segmental glomerulosclerosis (FSGS). FSGS is associated with loss of podocytes, an unusual cell type critical for the kidney's blood filtration function. Podocytes form interdigitating foot pro...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
08 Dec 2017
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| In: |
Science
Year: 2017, Volume: 358, Issue: 6368, Pages: 1332-1336 |
| ISSN: | 1095-9203 |
| DOI: | 10.1126/science.aal4178 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1126/science.aal4178 Verlag, Volltext: http://science.sciencemag.org/content/358/6368/1332 
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| Author Notes: | Yiming Zhou, Philip Castonguay, Eriene-Heidi Sidhom, Abbe R. Clark, Moran Dvela-Levitt, Sookyung Kim, Jonas Sieber, Nicolas Wieder, Ji Yong Jung, Svetlana Andreeva, Jana Reichardt, Frank Dubois, Sigrid C. Hoffmann, John M. Basgen, Mónica S. Montesinos, Astrid Weins, Ashley C. Johnson, Eric S. Lander, Michael R. Garrett, Corey R. Hopkins, Anna Greka |
| Summary: | Gaining a foothold on kidney disease? The leading cause of kidney disease worldwide is known as focal segmental glomerulosclerosis (FSGS). FSGS is associated with loss of podocytes, an unusual cell type critical for the kidney's blood filtration function. Podocytes form interdigitating foot processes that wrap around capillaries and prevent leakage of plasma proteins into urine (proteinuria). Zhou et al. suppressed proteinuria by preventing podocyte loss in two different rat models of kidney disease, using a compound that selectively inhibits the TRPC5 ion channel (see the Perspective by Chung and Shaw). In short-term studies, this compound had no detectable side effects. Thus, TRPC5 inhibitors may merit exploration as a therapy for progressive kidney disease. Science, this issue p. 1332; see also p. 1256. 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. A drug inhibits kidney disease in rat models by preventing loss of podocytes, cells critical for blood filtration. A drug inhibits kidney disease in rat models by preventing loss of podocytes, cells critical for blood filtration. |
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| Item Description: | Gesehen am 10.12.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1095-9203 |
| DOI: | 10.1126/science.aal4178 |