Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms

Insulin resistance is a key mechanism for diabetic glomerulopathy. Disruption in the molecular communication between glomerular podocytes and endothelia is critical in the progression of DN. Raised (but not too elevated) mitochondrial superoxide cellular levels in parallel with healthy mitochondria are protective against progression of diabetic kidney disease. A reduction in maximal mitochondrial respiration and reserve capacity could represent an important driving force for kidney disease progression in diabetes. Inhibition of SGLT2-mediated sodium-coupled glucose transport confers renoprotection of a similar magnitude to that of inhibitors of the renin–angiotensin–aldosterone system. Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) globally, and novel treatments are urgently needed. Current therapeutic approaches for diabetic nephropathy (DN) are focussing on blood pressure control with inhibitors of the renin–angiotensin–aldosterone system, on glycaemic and lipid control, and life-style changes. In this review, we highlight new molecular insights aiding our understanding of the initiation and progression of DN, including glomerular insulin resistance, dysregulation of cellular substrate utilisation, podocyte–endothelial communication, and inhibition of tubular sodium coupled glucose reabsorption. We believe that these mechanisms offer new therapeutic targets that can be exploited to develop important renoprotective treatments for DN over the next decade. Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) globally, and novel treatments are urgently needed. Current therapeutic approaches for diabetic nephropathy (DN) are focussing on blood pressure control with inhibitors of the renin–angiotensin–aldosterone system, on glycaemic and lipid control, and life-style changes. In this review, we highlight new molecular insights aiding our understanding of the initiation and progression of DN, including glomerular insulin resistance, dysregulation of cellular substrate utilisation, podocyte–endothelial communication, and inhibition of tubular sodium coupled glucose reabsorption. We believe that these mechanisms offer new therapeutic targets that can be exploited to develop important renoprotective treatments for DN over the next decade.