Role of thrombin in diabetic nephropathy. Sustained hyperglycemia results in diabetic nephropathy characterized by apoptosis of glomerular cells and loss and dysfunction of podocytes and albuminuria. Left side: High thrombin concentrations can induce disruption of the physiologic vascular barrier by an effect on protease activated receptor (PAR)1-dependent signaling via sphingosine 1 phosphate S1P receptor 3 (S1P3). High thrombin levels can also cause enhanced apoptosis of podocytes (not depicted in the figure). Right side: Low thrombin concentrations and the presence of activated protein C (APC) cause barrier protective effects via PAR1-dependent activation of another S1P receptor, S1P1. Both low thrombin levels and APC inhibit apoptosis of endothelial cells, as well as apoptosis and loss and dysfunction of podocytes, resulting in reduced albuminuria. Thrombin bound to thrombomodulin (TM) is essential for APC generation, a process augmented by the presence of the endothelial cell protein C receptor (EPCR). In this of Blood, Wang and colleagues4 show that the Factor V Leiden mutation, which is associated with modestly elevated thrombin generation, protects against diabetic nephropathy by mechanisms indicated in the right panel of the figure. Professional illustration by Marie Dauenheimer.
