Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy

Abstract

The current study hypothesized that alteration of the Akt signaling pathway by hyperglycemia may contribute to p38 MAPK activation and development of diabetic nephropathy. Immunoblot analysis demonstrated a hyperglycemia-induced increase in Akt phosphorylation in diabetic kidneys at 1 mo, peaking at 3 mo, and dropping back to baseline by 6 mo. Immunohistochemical staining with anti-pAkt antisera localized Akt phosphorylation to renal tubules. Maximal p38 MAPK phosphorylation was detected concomitant with increase in terminal uridine deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity in 6-mo diabetic kidneys. Exposure of cultured RPTCs to high glucose (HG; 22.5 mM) significantly increased Akt phosphorylation at 3, 6, and 9 h, and decreased thereafter. In contrast, p38 MAPK phosphorylation was detected between 9 and 48 h of HG treatment. Increased p38 MAPK activation at 24 and 48 h coincided with increased apoptosis, demonstrated by increased caspase-3 activity at 24 h and increased TUNEL-positive cells at 48 h of HG exposure. Blockade of p38 cascade with SB203850 inhibited HGinduced caspase-3 activation and TUNEL-positive cells. Overexpression of constitutively active Akt abrogated HG-induced p38 MAPK phosphorylation and RPTC apoptosis. In addition, blockade of the phosphatidylinositol-3 kinase/Akt pathway with LY294002 and silencing of Akt expression with Akt small interfering RNA induced p38 MAPK phosphorylation in the absence of HG. These results collectively suggest that downregulation of Akt activation during long-term hyperglycemia contributes to enhanced p38 MAPK activation and RPTC apoptosis. Mechanism of downregulation of Akt activation in 6-mo streptozotocin diabetic kidneys was attributed to decreased Akt-heat shock protein (Hsp) 25, Akt-p38 interaction, and decreased PTEN activity. Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK-mediated diabetic complications. diabetes mellitus; apoptotic cell death; renal inflammation THE SERINE/THREONINE KINASE Akt regulates a number of cellular functions, including glucose metabolism, glycogen synthesis, protein synthesis, cell proliferation, cell hypertrophy, and cell death (42). Akt is an important mediator of insulin action. Upon insulin stimulation, Akt regulates uptake of glucose in muscle, adipocytes, the liver, and other tissues by promoting translocation of glucose transporters from intracellular stores to the plasma membrane. In addition, Akt has been identified as an essential gene required for maintenance of normal glucose homeostasis. Mice lacking this gene develop insulin resistance as seen in type 2 diabetes (8). Akt has been investigated for its role in hyperglycemia-induced renal glomerular hypertrophy and apoptosis. However, contributions of the Akt pathway to hyperglycemia-induced renal tubular damage in type 1 diabetes have not received much attention.Diabetes is the leading cause of end-stage renal disease, and 10 -21% of all ...

Vasopressin inhibits apoptosis in renal collecting duct cells

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“…As hyperglycaemia and HNE can trigger multiple signalling pathways [22,[26][27][28][29], in order to confirm the direct effect of WNT activation on renal fibrogenesis in diabetic nephropathy, primary HRPTC were exposed to WNT3A-conditioned medium (WCM); plain L cell conditioned medium (LCM) was used as a control. As shown by western blot analysis, WCM increased cytosolic and nuclear β-catenin levels significantly compared with LCM ( Fig.…”

Curcumin induces the apoptosis of A549 cells via oxidative stress and MAPK signaling pathways

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