Podocyte Integrin- β 3 and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology 2020-08, Vol.31 (8), p.1762-1780
• Main Authors: Madhusudhan, Thati, Ghosh, Sanchita, Wang, Hongjie, Dong, Wei, Gupta, Dheerendra, Elwakiel, Ahmed, Stoyanov, Stoyan, Al-Dabet, Moh'd Mohanad, Krishnan, Shruthi, Biemann, Ronald, Nazir, Sumra, Zimmermann, Silke, Mathew, Akash, Gadi, Ihsan, Rana, Rajiv, Zeng-Brouwers, Jinyang, Moeller, Marcus J, Schaefer, Liliana, Esmon, Charles T, Kohli, Shrey, Reiser, Jochen, Rezaie, Alireza R, Ruf, Wolfram, Isermann, Berend
• Format: Article
• Language: English
• Subjects: Animals; Cytoprotection; Diabetic Nephropathies - prevention & control; Endothelial Protein C Receptor - physiology; GTP-Binding Protein alpha Subunits, G12-G13 - physiology; HEK293 Cells; Humans; Integrin beta3 - physiology; Mice; Mice, Inbred C57BL; Podocytes - physiology; Protein C - physiology; Receptor, PAR-1 - physiology; rhoA GTP-Binding Protein - physiology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2019111163

Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease-dependent signaling modulates dNP, in part 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. A combination of approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP. The zymogen protein C and aPC bind to podocyte integrin- , a subunit of integrin- . Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin- induces transient binding of integrin- with G and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin- its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin- , aPC induces sustained RhoA activation, mimicking the effect of thrombin. , overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC-integrin- interaction by specifically deleting podocyte integrin- 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-aPC and wild-type mice. aPC-integrin- acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin- as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.