Kidney Week

Abstract: TH-OR014

Novel Rho-Associated Coiled Kinase 2 Inhibitor (ANG4201) Reduces Renal Fibrosis and Improves Kidney Function in Subtotal Nephrectomy Mice Model

Session Information

• CKD: Mechanisms of Kidney Fibrosis
  October 25, 2018 | Location: 9, San Diego Convention Center
  Abstract Time: 05:06 PM - 05:18 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Ali, Quaisar, Angion Biomedica Corp., Uniondale, New York, United States

Quaisar Ali, PhD

• Dana, Dibyendu, Angion Biomedica Corp., Uniondale, New York, United States

Dibyendu Dana,

• Narayan, Prakash, Angion Biomedica Corp., Uniondale, New York, United States

Prakash Narayan,

• Li, An-Hu, Angion Biomedica Corp., Uniondale, New York, United States

An-Hu Li,

• Gadhiya, Satishkumar V., Angion Biomedica Corp., Uniondale, New York, United States

Satishkumar V. Gadhiya,

• Li, Jingsong, Angion Biomedica Corp., Uniondale, New York, United States

Jingsong Li,

• Lim, Dong sung, Angion Biomedica Corp., Uniondale, New York, United States

Dong sung Lim,

• Jung, Dawoon, Angion Biomedica Corp., Uniondale, New York, United States

Dawoon Jung,

• Paka, Latha, Angion Biomedica Corp., Uniondale, New York, United States

Latha Paka,

• Yamin, Michael A., Angion Biomedica Corp., Uniondale, New York, United States

Michael A. Yamin,

• Goldberg, Itzhak D., Angion Biomedica Corp., Uniondale, New York, United States

Itzhak D. Goldberg,

Background

Rho associated coiled kinase 1 (ROCK1) and 2 (ROCK2) are implicated in variety of cellular processes including organ fibrosis. Earlier we demonstrated that kidney ROCK2 and not ROCK1 is upregulated in animal models of renal fibrosis. The present study was done to investigate if inhibiting ROCK2 reduces renal fibrosis and improves kidney function.

Methods

Using core hopping and structure based drug design approach, we synthesized highly selective (>200 fold for ROCK2 vs ROCK1), orally bioavailable ROCK2 inhibitor (ANG4201). We evaluated the antifibrotic effects of ANG4201 in subtotal nephrectomy (Nx) mice model. Adult male SV129 mice were subjected to Nx, wherein poles of one kidney were ablated and contralateral kidneys were removed after two weeks. The Nx were then randomized to vehicle or ANG4201 (20 mg/Kg, PO, BID) and treated for 8 weeks. A week prior to sacrifice, GFR was measured by using FITC-Inulin clearance method. Blood pressure was measured by direct cannulation of the carotid artery. Kidney tissues were analyzed for fibrotic, molecular and inflammatory markers.

Results

Compared to control, Nx mic exhibited increase in both renal ROCK2 expression and phosphorylation of myosin phosphatase, a downstream marker of ROCK2 activity. Treating Nx mice with ANG4201 blocked the upregulation of these proteins. The increase in ROCK2 activity correlated with increase in renal fibrosis characterized by increase in kidney hydroxyproline and α-SMA expression. Nx mice also had elevated blood pressure (MAP; ~165 mm Hg). Intervention with ANG4201 did not affect blood pressure but attenuated hydroxyproline and α-SMA expression which were confirmed with Mason’s trichrome and Picrosirius red staining. The reduction in fibrosis was associated with significant improvement in GFR by ~38%, measured by FITC-Inulin clearance method. Urinary EGF, marker of renal function loss was found to be elevated in Nx and subsequently reduced with ANG4201 treatment.

Conclusion

This study demonstrates that ROCK2 upregulation contributes to renal fibrosis and renal functional loss in subtotal nephrectomy mice model. ANG4201 is highly promising orally bioavailable therapeutic ROCK2 inhibitor with potential use in chronic kidney disease.

Funding

• NIDDK Support