Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets

Abstract

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. The standard treatments for diabetic patients are glucose and blood pressure control, lipid lowering, and renin-angiotensin system blockade; however, these therapeutic approaches can provide only partial renoprotection if started late in the course of the disease. One major limitation in developing efficient therapies for DN is the complex pathobiology of the diabetic kidney, which undergoes a set of profound structural, metabolic and functional changes. Despite these difficulties, experimental models of diabetes have revealed promising therapeutic targets by identifying pathways that modulate key functions of podocytes and glomerular endothelial cells. In this review we will describe recent advances in the field, analyze key molecular pathways that contribute to the pathogenesis of the disease, and discuss how they could be modulated to prevent or reverse DN.

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…Such is indeed the case in diabetic kidney disease (DKD) whereby oxidative stress is elevated and mitochondrial dysfunction is aggravated, leading to renal injury [ 7 , 8 ]. DKD, also known as diabetic nephropathy [ 9 , 10 , 11 , 12 , 13 ], is a common complication of diabetic mellitus, including both type 1 and type 2 diabetes. While type 1 diabetes is caused by lack of insulin due to pancreatic β cell destruction [ 14 , 15 , 16 ], type 2 diabetes could be caused by insulin resistance or insulin deficiency [ 17 , 18 , 19 , 20 , 21 , 22 ].…”

PPAR-α Agonist Fenofibrate Prevented Diabetic Nephropathy by Inhibiting M1 Macrophages via Improving Endothelial Cell Function in db/db Mice

“…Db/db group presented higher UACR than db/m and db/m+F groups, and db/db+F group had the significantly lower UACR level than db/db group. Diabetes causes glomerular mesangial expansion and glomerulosclerosis in kidneys, and leads to glomerular podocyte injury ( 41 ). In current research, these pathological changes were found in mouse kidneys of db/db group, while fenofibrate improved these injuries in mouse kidneys of db/db+F group.…”

Activated Histone Acetyltransferase p300/CBP-Related Signalling Pathways Mediate Up-Regulation of NADPH Oxidase, Inflammation, and Fibrosis in Diabetic Kidney

“…Over the past two decades, multiple molecular triggers and signalling pathways of glomerular capillary dysfunction contributing to kidney failure have been determined [ 1 , 2 , 3 ]. Yet, despite the significant advances in clinical and experimental research in diabetes and its complications, the diagnosis and effective treatment of DKD remains challenging [ 4 , 5 , 6 , 7 , 8 ]. Noteworthy, due to the metabolic memory in diabetes (an emergent and rapidly evolving epigenetic-related mechanistic concept) and in spite of the therapeutic control of hyperglycaemia, diabetes pathological long-lasting effects persist and continue to promote systemic cellular detrimental effects [ 44 , 45 , 46 , 47 ].…”

“…Diabetic kidney disease (DKD), the major microvascular complication of both type I and type II diabetes, is a complex multifactorial renal disorder having a detrimental impact on the patient’s quality of life and life-span expectation [ 1 , 2 , 3 ]. Dysfunction of glomerular endothelial cells and podocytes, thickening of the glomerular basement membrane, mesangial cells hypertrophy and proliferation, progressive accumulation of mesangial extracellular matrix (ECM) components, podocyte damage, and disruption of glomerular endothelium fenestrations are the main structural alterations ultimately leading to glomerulosclerosis; a pathological condition that is further responsible for increased intraglomerular capillary pressure, hyperfiltration, and eventually kidney failure [ 4 , 5 , 6 ].…”