Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) together with glomerular hyperfiltration has been implicated in the development of diabetic microangiopathy in the initial stage of diabetic diseases. Increased amounts of urinary protein in DN may be associated with functional and morphological alterations of podocyte, mainly including podocyte hypertrophy, epithelial-mesenchymal transdifferentiation (EMT), podocyte detachment, and podocyte apoptosis. Accumulating studies have revealed that disruption in multiple renal signaling pathways had been critical in the progression of these pathological damages, such as adenosine monophosphate-activated kinase signaling pathways (AMPK), wnt/β-catenin signaling pathways, endoplasmic reticulum stress-related signaling pathways, mammalian target of rapamycin (mTOR)/autophagy pathway, and Rho GTPases. In this review, we highlight new molecular insights underlying podocyte injury in the progression of DN, which offer new therapeutic targets to develop important renoprotective treatments for DN over the next decade.

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

“…Kidney macroautophagy is regulated by mammalian target of rapamycin (mTOR) [8,38,39], AMP-activated protein kinase (AMPK) [8], SIRT1 [8], Wnt/β-catenin [40], and TGF-β [41] signaling pathways. The downregulation of glomerular autophagy under hyperglycemic condition is considered a result of activation of mTOR pathway [8,42] or suppression of AMPK activity and SIRT1 signaling [37,43,44]. In our study, glomerular autophagy was related negatively to parameters of glycemic status, fructosamine and glycated albumin.…”

“…Glomeruli from mice with podocyte-specific knockout of GLUT4 are protected from diabetes-induced hypertrophy, mesangial expansion and albuminuria, and fail to activate the mTOR pathway [51]. The latter is activated in podocytes in diabetic conditions that decrease autophagy activity [42]. Interestingly, rapamycin-induced autophagy increased the glucose uptake in the podocytes and phosphorylated insulin receptor, which caused an increase in insulin sensitivity [24].…”

Inhibition of high mobility group box 1 (HMGB1) attenuates podocyte apoptosis and epithelial‐mesenchymal transition by regulating autophagy flux

“…Increased urinary protein excretion in patients is the major hallmark of early DN and is accompanied by EMT progression and apoptotic programmed cell death in podocytes. 4 Multiple renal signaling transduction pathways participate in the progression of detrimental changes to podocytes, including activation of Forkhead box protein O4 (FOXO4)/p38 and Notch signaling and inhibition of phosphatidylinositol-3 kinase (PI3K)/protein kinase signaling. [5][6][7] Autophagy dysfunction of podocytes is another essential factor inducing podocyte injury.…”

Ramipril and resveratrol co‐treatment attenuates RhoA/ROCK pathway‐regulated early‐stage diabetic nephropathy‐associated glomerulosclerosis in streptozotocin‐induced diabetic rats

“…Diabetic nephropathy (DN) is a cause of end‐stage renal disease, and the major characteristics of DN are glomerulosclerosis and tubulointerstitial fibrosis . A high glomerular filtration rate underlies the basic pathophysiology of DN and can lead to high blood pressure within the glomeruli and glomerular hyperfiltration . Generally, in early‐stage DN (stage I), glomerular ultrafiltration is indicated by a glomerular filtration rate of >150 mL/min × 1.73 m 2 , and disease progression eventually leads to thickening of the glomerular basement membrane.…”