Pathophysiology of Diabetic Nephropathy

Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Although debated for many years whether haemodynamic or structural changes are more important in the development of diabetic nephropathy, it is now clear that these processesare interwoven and present two sides of one coin. On a molecular level, hyperglycaemia andproteins altered by high blood glucose such as Amadori products and advanced glycationend-products (AGEs) are key players in the development of diabetic nephropathy. Recentevidence suggests that an increase in reactive oxygen species (ROS) formation induced byhigh glucose-mediated activation of the mitochondrial electron-transport chain is an earlyevent in the development of diabetic complications. A variety of growth factors and cytokinesare then induced through complex signal transduction pathways involving protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-KB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines, particularly, TGF- isimportant in the development of renal hypertrophy and accumulation of extracellular matrixcomponents. Activation of the renin-angiotensin system by high glucose, mechanical stress, and proteinuria with an increase in local formation of angiotensin II (ANG II) causes manyof the pathophysiological changes associated with diabetic nephropathy. In fact, it has beenshown that angiotensin II is involved in almost every pathophysiological process implicatedin the development of diabetic nephropathy (haemodynamic changes, hypertrophy, extracellularmatrix accumulation, growth factor/cytokine induction, ROS formation, podocytedamage, proteinuria, interstitial inflammation).