Podocyte Integrin-β₃ and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Diabetic nephropathy (dNP) is a leading cause of end-stage kidney disease (ESKD) with limited therapeutic options.
• Coagulation protease signaling, particularly through protease-activated receptors (PARs), influences dNP.
• The cytoprotective role of activated protein C (aPC) in dNP is established, but its underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of the activated protein C (aPC)-integrin interaction in the pathogenesis and potential treatment of diabetic nephropathy (dNP).
• To elucidate the signaling pathways modulated by aPC and integrin-αvβ3 in podocytes during dNP.

Main Methods:

• Utilized a combination of in vitro cell culture and in vivo mouse models to study aPC-integrin interactions in dNP.
• Assessed the binding of protein C and aPC to podocyte integrin-αvβ3.
• Evaluated the impact of integrin-β3 deficiency and aPC's RGD sequence on RhoA signaling and nephroprotection in mouse models of dNP.

Main Results:

• Activated protein C (aPC) and its zymogen bind to podocyte integrin-αvβ3.
• aPC-integrin-αvβ3 interaction transiently regulates PAR-dependent RhoA signaling in podocytes, which is essential for its protective effect in dNP.
• Disruption of this interaction leads to sustained RhoA activation and loss of aPC's nephroprotective benefits.
• Pharmacologic inhibition of PAR1, a key thrombin receptor, restricted RhoA activation and provided nephroprotection.

Conclusions:

• Integrin-αvβ3 acts as a critical coreceptor for aPC, functioning as a rheostat to control PAR1-dependent RhoA activation in podocytes within the context of diabetic nephropathy (dNP).
• The aPC-integrin-αvβ3 complex is essential for mediating the nephroprotective signaling of aPC in dNP.
• Targeting the aPC-integrin-αvβ3 pathway represents a potential therapeutic strategy for dNP.