K) pathways, controlling cell proliferation, differentiation, and apoptosis (146). EGFR is broadly
K) pathways, controlling cell proliferation, differentiation, and apoptosis (146). EGFR is broadly expressed in mammalian kidney, like glomeruli, proximal tubules, and cortical and medullary collecting ducts (179), and expression increases in both BD2 site glomeruli and tubules in response to diabetes. Provided recent research indicating tubule lomerular interactions underlying diabetic nephropathy (20), it is likely that EGFR might be playing a pathogenic function in many cell types of the nephron. Studies by our laboratory and others assistance a part for EGFR ERK8 supplier activation as a crucial mediator of renal repair following acute injury (9), but outcomes by us and other people have also ascribed a detrimental part to persistent EGFR activation in progressive renal fibrosis induced by subtotal nephrectomy (21), unilateral ureteral obstruction (22),diabetes.diabetesjournals.orgZhang and AssociatesFigure 7–EGFR inhibition stimulated AMPK activity but inhibited S6K activity in mesangial cells. A: AG1478 (300 nmol/L) effectively inhibited EGFR phosphorylation in mesangial cells cultured in high-glucose medium (25 mmol/L). B: AG1478 therapy for six h led to inhibition of S6K activity and stimulation of AMPK activity. *P 0.05; **P 0.01 vs. manage group; n = 3.renovascular hypertension (23), or renal injury induced by angiotensin II (two) or endothelin (24). The existing research indicate an important part for EGFR activation in mediating diabetic nephropathy at the same time. Our getting of a protective role for erlotinib concurs using a preceding study in renin-transgenic rats, in which PKI 166, a structurally different EGFR inhibitor, was also located to inhibit diabetic nephropathy (25). In preliminary research, we also located comparable protection against progression of diabetic nephropathy using a third EGFR inhibitor, gefitinib. Elevated ER tension has been linked to the improvement of diabetic nephropathy, and chemical chaperones, which decrease misfolded proteins and thereby mitigate ER stress, have already been shown to ameliorate STZ-induced diabetic nephropathy (26). The role of autophagy in diabetic nephropathy is still incompletely understood. While some investigators have recommended that autophagy could play a pathogenic part (27), other people have suggested that autophagy is protective (28). Podocytes have higher basal levels of autophagy (29), and in this regard, we and other individuals have recently reported that inhibition of podocyte autophagy by targeting autophagy-specific class III PI3K results in progressive glomerulosclerosis (30). mTOR activity increases in podocytes in diabetic mice and correlates with increased ER tension and progressive glomerulosclerosis (31). In addition to glomeruli, persistent mTOR activation has also been linked with apoptosis of renal tubule cells in diabetes (32). Renal mTOR activation in poorly controlled diabetes may perhaps result from a combination of AKT inhibition of tuberous sclerosis complicated 2, hyperglycemia-induced AMPK inhibition, andincreased glucose uptake via glucose transporter 1, in which the resulting improved glycolysis and activation of GAPDH can lead straight to Rheb activation of mTOR by lowering Rheb binding to GAPDH (33,34). EGFR activation is a well-described mediator of mTOR activity through activation in the PI3K/AKT pathway (35,36). Furthermore, EGFR activation inhibits renal gluconeogenesis and stimulates glycolysis in proximal tubule (37,38) and has been reported to enhance glucose transporter 1 expression in mesangial cells (39).