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. 2017 Dec 8;358(6368):1332-1336.
doi: 10.1126/science.aal4178.

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

Yiming Zhou  1   2 , Philip Castonguay  1   2 , Eriene-Heidi Sidhom  1   2 , Abbe R Clark  1   2 , Moran Dvela-Levitt  1   2 , Sookyung Kim  1   2 , Jonas Sieber  1   2 , Nicolas Wieder  1   2 , Ji Yong Jung  1   3 , Svetlana Andreeva  1 , Jana Reichardt  1 , Frank Dubois  1 , Sigrid C Hoffmann  4 , John M Basgen  5 , Mónica S Montesinos  1   2 , Astrid Weins  1   6 , Ashley C Johnson  7 , Eric S Lander  2 , Michael R Garrett  7 , Corey R Hopkins  8 , Anna Greka  1   2
Affiliations

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

Yiming Zhou et al. Science. .

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.

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Figures

Fig. 1
Fig. 1. Escalating TRPC5 ion channel activity correlates with disease progression, and TRPC5 inhibition rescues podocytes in AT1R Tg rats
(A) ML204 (1 μM) blocks TRPC5 single-channel activity induced by Riluzole (Rilu, 3 μM) in inside-out recordings from rat glomeruli isolated during early disease (Onset), as compared to barely detectable current in age-matched WT glomeruli (Onset). ML204 blocks a significantly greater Rilu-activated conductance in glomeruli from rats with established disease (Advanced), compared to minimal TRPC5 activity in age-matched WT glomeruli (Advanced). C, close state; O1, open channel level 1; O2, open channel level 2. Vm = −60 mV. (B) Quantification of open channel probability (NPo) for the conductances recorded in (A). WT Rilu n = 4 and 5, WT Rilu + ML204 n = 4 and 5, AT1R Tg Rilu n = 4 and 5, AT1R Tg Rilu + ML204 n = 4 and 5 for Onset and Advanced groups, respectively. Mean ± SEM, *P < 0.05, **P < 0.01. (C) TRPC6 channel activity contributes to podocyte Ca2+ homeostasis. TRPC5 activity is coincident with onset of proteinuria and correlates with FSGS disease progression. (D) Progressive proteinuria suppressed by twice-per-day i.p. administration of ML204 in the Advanced cohort of AT1R Tg rats treated for 14 days. AT1R Tg PBS n = 23, AT1R Tg ML204 n= 23. Mean ± SEM, *P < 0.05, **P < 0.01. (E) Rescue of podocyte numbers in vivo in ML204-treated AT1R Tg rats with established disease (Advanced). WT PBS n = 7, AT1R Tg PBS n = 8, AT1R Tg ML204 n = 8. Mean ± SEM, **P < 0.01.
Fig. 2
Fig. 2. AC1903, a specificTRPC5 small-molecule inhibitor, protects podocytes from ROS-mediated injury
(A) Chemical structure of AC1903. (B) Selectivity of AC1903 (1 to 100 μM) for TRPC5 over TRPC4 and TRPC6 in dose-response patch-clamp experiments in the whole-cell configuration. n > 3 for each dose. Mean ± SEM. (C) Equipotency between AC1903 and ML204 in dose-response patch-clamp experiments in the whole-cell configuration in response to Rilu (3 μM). ML204 n >3, AC1903 n > 3 for each dose Mean ± SEM. (D) ROS generation blocked by AC1903 (30 μM) in vitro in WT podocytes treated with AngII (10 μM). DMSO, dimethyl sulfoxide; Veh, vehicle. DMSO + Veh n = 23, Ang II + Veh n = 23, Ang II + AC1903 n = 24, Ang II + NAC n = 24, each from three independent replicates. Mean ± SEM, ***P < 0.001. (E) ROS generation blocked by AC1903 (30 μM), ML204 (30 μM), and NSC23677 (50 μM) in vitro in caAT1R-expressing podocytes. Veh n = 40 and 60; ML204 n = 40 and 60; AC1903 n = 40 and 60; NSC23677 n = 40 and 60, for control and caAT1R-expressing podocytes, respectively, each from four independent replicates. Mean ± SEM, **P < 0.01. (F) Podocyte cell death rescued by AC1903 (30 μM), ML204 (30 μM), and NSC23677 (50 μM). Control n = 24, Veh n = 24, ML204 n = 24, AC1903 n = 24, NSC23677 n = 12, each from four independent replicates. Mean ± SEM, *P < 0.05.
Fig. 3
Fig. 3. AC1903 suppresses proteinuric kidney disease progression and rescues podocytes in AT1R Tg rats with advanced disease
(A) AC1903 (50 mg/kg) ameliorates proteinuria in AT1R Tg rats with established, advanced disease. Veh n = 13, AC1903 n = 14. Mean ± SEM, ***P < 0.001. (B) AC1903 inhibition of TRPC5 channel activity in insideout recordings from advanced-disease AT1R rat glomeruli. (C) Quantification of open channel probability (NPo) for the conductances recorded in (B). Each n = 6. Mean ± SEM, *P < 0.05. (D) Toluidine blue semithin sections of rat kidneys. Red asterisks indicate pseudocysts. Bar, 50 μM. (E) Reduction of pseudocyst volume in AT1R Tg AC1903 rats compared to AT1R Tg vehicle rats. WT Veh n = 7, AT1R Tg Veh n = 7, AT1R Tg AC1903 n = 7. Mean ± SEM, *P < 0.05, **P < 0.01. (F) Rescue of podocyte numbers in vivo in AC1903-treated AT1R Tg rats with established disease (Advanced). WT Veh n = 7, AT1R Tg Veh n = 7, AT1R Tg AC1903 n = 7, Advanced. Mean ± SEM, *P < 0.05.
Fig. 4
Fig. 4. AC1903 suppresses proteinuric kidney disease progression and rescues podocytes in hypertensive Dahl S rats
(A) AC1903 (50 mg/kg) ameliorates proteinuria in Dahl S rats when administered at the same time as high salt intake (Onset). Veh n = 8, AC1903 n = 8. Mean ± SEM, ***P < 0.001. (B) AC1903 (50 mg/kg) suppresses proteinuria in Dahl S rats with established, advanced disease (Advanced). Veh n = 9, AC1903 n = 14. Mean ± SEM, ***P < 0.001. (C) Rescue of podocyte numbers in vivo in AC1903-treated Dahl S rats with established disease (Advanced). Veh n = 9, AC1903 n = 14. Mean ± SEM, *P < 0.05. (D) Administration of AC1903 has no detectable effect on mean arterial pressure (MAP) of Dahl S rats. Veh n = 9, AC1903 n = 14. Mean ± SEM.
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