A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

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

doi:10.1126/science.aal4178

A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

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. HopkinsAnna Greka

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134 Scopus citations

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	https://doi.org/10.1126/science.aal4178
State	Published - 8 Dec 2017
Externally published	Yes

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© 2017, American Association for the Advancement of Science. All rights reserved.

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Zhou, Y., Castonguay, P., Sidhom, E. H., Clark, A. R., Dvela-Levitt, M., Kim, S., Sieber, J., Wieder, N., Jung, J. Y., Andreeva, S., Reichardt, J., Dubois, F., Hoffmann, S. C., Basgen, J. M., Montesinos, M. S., Weins, A., Johnson, A. C., Lander, E. S., Garrett, M. R., ... Greka, A. (2017). A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science, 358(6368), 1332-1336. https://doi.org/10.1126/science.aal4178

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title = "A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models",

abstract = "Progressive kidney diseases are often associated with scarring of the kidney{\textquoteright}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.",

author = "Yiming Zhou and Philip Castonguay and Sidhom, {Eriene Heidi} and Clark, {Abbe R.} and Moran Dvela-Levitt and Sookyung Kim and Jonas Sieber and Nicolas Wieder and Jung, {Ji Yong} and Svetlana Andreeva and Jana Reichardt and Frank Dubois and Hoffmann, {Sigrid C.} and Basgen, {John M.} and Montesinos, {M{\'o}nica S.} and Astrid Weins and Johnson, {Ashley C.} and Lander, {Eric S.} and Garrett, {Michael R.} and Hopkins, {Corey R.} and Anna Greka",

year = "2017",

month = dec,

day = "8",

doi = "10.1126/science.aal4178",

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Zhou, Y, Castonguay, P, Sidhom, EH, Clark, AR, Dvela-Levitt, M, Kim, S, Sieber, J, Wieder, N, Jung, JY, Andreeva, S, Reichardt, J, Dubois, F, Hoffmann, SC, Basgen, JM, Montesinos, MS, Weins, A, Johnson, AC, Lander, ES, Garrett, MR, Hopkins, CR & Greka, A 2017, 'A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models', Science, vol. 358, no. 6368, pp. 1332-1336. https://doi.org/10.1126/science.aal4178

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T1 - A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

AU - Zhou, Yiming

AU - Castonguay, Philip

AU - Sidhom, Eriene Heidi

AU - Clark, Abbe R.

AU - Dvela-Levitt, Moran

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AU - Sieber, Jonas

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AU - Reichardt, Jana

AU - Dubois, Frank

AU - Hoffmann, Sigrid C.

AU - Basgen, John M.

AU - Montesinos, Mónica S.

AU - Weins, Astrid

AU - Johnson, Ashley C.

AU - Lander, Eric S.

AU - Garrett, Michael R.

AU - Hopkins, Corey R.

AU - Greka, Anna

PY - 2017/12/8

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AB - 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.

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A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

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