Mechanisms of Synergistic Interactions of Diabetes and Hypertension in Chronic Kidney Disease: Role of Mitochondrial Dysfunction and ER Stress

Purpose of Review To discuss the importance of synergistic interactions of diabetes mellitus (DM) and hypertension (HT) in causing chronic kidney disease and the potential molecular mechanisms involved. Recent Findings DM and HTare the two most important risk factors for chronic kidney disease (CKD) and development of end-stage renal disease (ESRD). The combination of HTandDMmay synergistically promote the progression of renal injury through mechanisms that have not been fully elucidated. Hyperglycemia and other metabolic changes in DM initiate endoplasmic reticulum (ER) stress and mitochondrial (MT) adaptation in different types of glomerular cells. These adaptations appear to make the cells more vulnerable to HT-induced mechanical stress. Excessive activation of mechanosensors, possibly via transient receptor potential cation channel subfamily C member 6 (TRPC6), may lead to impaired calcium (Ca2+) homeostasis and further exacerbate ER stress and MT dysfunction promoting cellular apoptosis and glomerular injury. Summary The synergistic effects of HT and DM to promote kidney injury may be mediated by increased intraglomerular pressure. Chronic activation of mechanotransduction signaling may amplify metabolic effects of DM causing cellular injury through a vicious cycle of impaired Ca2+ homeostasis, mitochondrial dysfunction, and ER stress.