Podocyte Integrin-b3 and activated protein C coordinately restrict RhoA signaling and ameliorate diabetic nephropathy

Thati Madhusudhan, Sanchita Ghosh, Hongjie Wang, Wei Dong, Dheerendra Gupta, Ahmed Elwakiel, Stoyan Stoyanov, Moh'd Mohanad Al-Dabet, Shruthi Krishnan, Ronald Biemann, Sumra Nazir, Silke Zimmermann, Akash Mathew, Ihsan Gadi, Rajiv Rana, Jinyang Zeng-Brouwers, Marcus J. Moeller, Liliana Schaefer, Charles T. Esmon, Shrey KohliJochen Reiser, Alireza R. Rezaie, Wolfram Ruf, Berend Isermann

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease–dependent signaling modulates dNP, in part via the G protein–coupled, protease-activated receptors (PARs). Specifically, the cytoprotective protease-activated protein C (aPC) protects from dNP, but the mechanisms are not clear. Methods A combination of in vitro approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP. Results The zymogen protein C and aPC bind to podocyte integrin-b3, a subunit of integrin-avb3. Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin-avb3 induces transient binding of integrin-b3 with Ga13 and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin-b3 via its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin-b3, aPC induces sustained RhoA activation, mimicking the effect of thrombin. In vivo, overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC–integrin-b3 interaction by specifically deleting podocyte integrin-b3 or by abolishing aPC’s integrin-binding RGD sequence enhances RhoA signaling in mice with high aPC levels and abolishes aPC’s nephroprotective effect. Pharmacologic inhibition of PAR1, the pivotal thrombin receptor, restricts RhoA activation and nephroprotects RGE-aPChigh and wild-type mice. Conclusions aPC–integrin-avb3 acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin-avb3 as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.

Original languageEnglish (US)
Pages (from-to)1762-1780
Number of pages19
JournalJournal of the American Society of Nephrology
Volume31
Issue number8
DOIs
StatePublished - Aug 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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