Glomerular mesangial cell and podocyte injuries in diabetic nephropathy.

Diabetic nephropathy is one of the leading causes of end-stage renal disease and creates heavy healthcare burdens globally. Dysfunction of mesangial cells and podocytes contributes to diabetic nephropathy. Dysregulation of signaling involved in renal development and regeneration may cause diabetic kidney damages. Growing evidences suggest the importance of dysregulated dickkopf-1 (DKK1)/Wnt/ ß-catenin signaling pathways in the pathogenesis of diabetic glomerular injuries. The inhibition of Wnt signaling in injured mesangial cells is likely attributed to the high glucose-induced Ras/Rac1 dependent superoxide formation. When DKK1, the cellular inhibitor of Wnt signaling, binds to the Kremen-2 receptor, depositions of extracellular matrix increase in the mesangium of diabetic kidneys. Additionally, reactivation of Notch-1 signaling has been implicated in podocytopathy during diabetic proteinuria development. Knocking down Notch-1 alleviates vascular endothelial growth factor (VEGF) expression, nephrin repression and proteinuria in diabetic kidneys. It is also found that epigenetic modulations by histone deacetylase 4 (HDAC4) and miR-29a could lead to diabetic nephropathy. High glucose increases the expression of HDAC4, which causes deacetylation with subsequent ubiquitination of nephrin. Overexpression of miR-29a in diabetic transgenic mice would decrease the expression of HDAC4 and stabilize nephrin. Surprisingly, reprogramming or reactivation of signaling involved in renal development or regeneration often brings about diabetic glomerular sclerosis in mesangial cells and podocytes. Better knowledge about modifications of embryonic stem cell signaling will have a chance to implement strategically focused pharmacological research programs aiming to the development of new drugs for diabetic kidney injuries.

The Wnt Signaling Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca2+ and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca2+ signaling are critical for DN development.