TY - JOUR
T1 - Podocyte Integrin-b3 and activated protein C coordinately restrict RhoA signaling and ameliorate diabetic nephropathy
AU - Madhusudhan, Thati
AU - Ghosh, Sanchita
AU - Wang, Hongjie
AU - Dong, Wei
AU - Gupta, Dheerendra
AU - Elwakiel, Ahmed
AU - Stoyanov, Stoyan
AU - Al-Dabet, Moh'd Mohanad
AU - Krishnan, Shruthi
AU - Biemann, Ronald
AU - Nazir, Sumra
AU - Zimmermann, Silke
AU - Mathew, Akash
AU - Gadi, Ihsan
AU - Rana, Rajiv
AU - Zeng-Brouwers, Jinyang
AU - Moeller, Marcus J.
AU - Schaefer, Liliana
AU - Esmon, Charles T.
AU - Kohli, Shrey
AU - Reiser, Jochen
AU - Rezaie, Alireza R.
AU - Ruf, Wolfram
AU - Isermann, Berend
N1 - Publisher Copyright:
Copyright © 2020 by the American Society of Nephrology
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2019111163
DO - 10.1681/ASN.2019111163
M3 - Article
C2 - 32709711
AN - SCOPUS:85089125450
SN - 1046-6673
VL - 31
SP - 1762
EP - 1780
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 8
ER -