The regulation of endoplasmic reticulum stress by activated protein C in diabetic nephropathy

Abstract

Diabetic nephropathy is the leading cause of chronic kidney disease as well as the primary complication of diabetes worldwide. Although, the molecular function of endoplasmic reticulum (ER) stress in diabetes mellitus (DM) is well-established in the liver and the pancreas, the role of ER stress in diabetic nephropathy remained unknown when starting this project. We uncovered important pathophysiological consequences of insulin resistance and hyperglycemia towards maladaptive ER stress and its contributions to the progression of diabetic nephropathy (dNP). This study establishes causality between defective insulin signaling leading to maladaptive ER stress in podocytes and impaired kidney function in DM. Searching for potential pathways compensating for impaired insulin signaling, we identified a new role of the coagulation system. Coagulation protease signaling rescues defective insulin signaling in podocytes, thus, protecting these cells from the detrimental effects of hyperglycemia. Specifically, the coagulation protease activated protein C (aPC), known for its pleiotropic cytoprotective effects, activates the inositol-requiring enzyme 1α (IRE-1α) - spliced X-box-binding protein 1 (sXBP1) signaling arm of the adaptive unfolded protein response (UPR), restoring ER homeostasis. Insulin- and aPC-dependent signaling, despite acting through disjunct receptors, both signal through p85α/β- phosphatidylinositol 3-kinase (PI3K) to induce nuclear localization of sXBP1. Development of therapeutics that mimic aPC-signaling and restore ER homeostasis, or alterantive approaches to restore ER homeostasis in insulin resistant tissues constitute a new therapeutic approach in dNP.