ERK and p38 mediate high-glucose-induced hypertrophy and TGF-β expression in renal tubular cells

Abstract

We investigated the expression of ERK, p38 mitogen-activated protein kinase (p38), and JNK in renal tubules of diabetic rats following 3 wk after streptozotocin injection (DM). Although the expression of ERK was not different between controls and DM, phosphorylated ERK was expressed more intensely in DM. p38 And phosphorylated p38 were detected only in the diabetic kidney and were localized in all tubular segments. JNK and phosphorylated JNK were expressed similarly in controls and DM. Transforming growth factor (TGF)-beta was expressed in all tubular segments of DM, coinciding with the localization of p38. In LLC-PK1 cells, phosphorylation of ERK and p38 increased after 24- to 72-h exposure to high glucose (HG). Coincubation with a p38 inhibitor SB-203580 or a MEK inhibitor, PD-98059, suppressed the HG-induced increases in protein content, [3H]leucine incorporation, and the protein-to-DNA ratio. SB-203580 or PD-98059 also abolished the HG-stimulated expression of TGF-beta protein. These results demonstrate that ERK and p38 are activated in renal tubular cells of DM and may mediate HG-induced cellular hypertrophy and TGF-beta expression.

FOG2 Protein Down-regulation by Transforming Growth Factor-β1-induced MicroRNA-200b/c Leads to Akt Kinase Activation and Glomerular Mesangial Hypertrophy Related to Diabetic Nephropathy

“…ERK activation is known to be involved in TGF-␤-induced collagen expression as well as HGinduced cellular hypertrophy in mesangial cells (59 -61). Blockage of ERK by specific ERK inhibitors has been shown to attenuate high glucose-induced cellular hypertrophy and fibronectin expression in mesangial cells and renal tubular cells (62,63), suggesting ERK as one of the signaling pathways in the progression of DN along with Akt (64). However, the molecular mechanisms by which TGF-␤ activates ERK are not fully understood.…”

Epithelial sodium channel regulated by differential composition of a signaling complex

“…In the kidney, ERK1/2 is expressed in all nephron segments and plays an important role in multiple physiological (33) and pathological processes (30). In contrast to other nephron segments, ERK1/2 appears to have basal activity in distal nephron cells (31,34), consistent with tonic inhibition of Na ϩ transport by the ERK pathway. It is well demonstrated that the components of the MAPK cascade (Raf-1, MEK1/2, and ERK1/2, in this case) exist in a multiprotein complex to permit the cell to perform coordinate regulation of several simultaneous possibly divergent signals at multiple levels (35).…”

Diabetes and renal tubular cell apoptosis

“…Prolonged exposure (1-13 d) of proximal tubular epithelial cells to hyperglycemic environment has been shown to inhibit cell proliferation and induce growth arrest or cellular MINIREVIEWS apoptosis [8][9][10][11][12] . These cellular effects are caused by the activation of a network of intracellular signaling pathways and include the phosphatidylinostiol 3 kinase (PI3 kinase)/adams kara taylor (AKT) signaling pathway [13] .…”