[p38 MAPK mediates high glucose-induced renal tubular epithelial-mesenchymal transition.].

The aim of the present study was to investigate the role of p38 MAPK in the renal tubular epithelial-mesenchymal transition (TEMT) induced by high glucose. In in vivo study, the rats were randomly divided into control (C), diabetes mellitus (DM) and insulin-treated DM groups. Immunohistochemical staining and Western blot were employed to determine the expression of p38 MAPK and p-p38 MAPK protein in renal cortex of rats. In in vitro study, primary renal tubular epithelial cells (PTECs) were cultured with normal glucose (5.5 mmol/L), high glucose (20 mmol/L D-glucose), high osmolality (20 mmol/L D-mannitol) and SB202190 (a p38 MAPK inhibitor) plus high glucose respectively for 72 h. The expressions of p38 MAPK, p-p38 MAPK, Snail1, transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin (alpha-SMA) and E-cadherin protein and mRNA were detected by immunocytochemical staining, Western blot and RT-PCR. The p38 MAPK and p-p38 MAPK were specifically upregulated by high glucose in both in vivo and in vitro studies. The p38 MAPK activation was abolished by insulin controlling hyperglycemia to normal level in DM rats and inhibited dramatically by SB202190 in high glucose-cultured PTECs. The protein and mRNA of alpha-SMA were markedly increased in PTECs cultured with high glucose and were 12-fold and 8-fold respectively over that in the normal glucose, which were significantly suppressed by SB202190. SB202190 down-regulated the high glucose-induced Snail1 protein expression in PETCs, and restored partly the depression of E-cadherin protein and mRNA. These results suggest that p38 MAPK mediates high glucose-induced TEMT via transcription factor Snail1.

[Transforming growth factor-ß1 and Snail1 mediate tubular epithelial-mesenchymal transition in diabetic rats].

The present study was aimed to explore the expressions of transforming growth factor-ß1 (TGF-ß1) and Snail1 in renal tissues of diabetic rats, and their role in tubular epithelial-mesenchymal transition (TEMT). Induced diabetic rats were randomly divided into 2-, 4-, 8-, 12-, 16-, 20-, 24-week and 16wA, 20wA, 24wA groups. The rats in 16wA, 20wA and 24wA groups were treated with insulin to control blood glucose to the normal level from the 13th week. The age-matched rats were set as controls. Blood glucose, 24-hour urine protein, serum creatinine (Scr), kidney index of rats were measured. PAS staining was used to observe the renal pathological changes. Immunohistochemical staining and (or) Western blot were employed to determine the expressions of TGF-ß1, Snail1, E-cadherin, α-smooth muscle actin (α-SMA) and fibronectin (FN) proteins. The expressions of Snail1 and E-cadherin mRNAs in renal cortex were examined by RT-PCR. Blood glucose, 24-hour urine protein, Scr and kidney index increased remarkably in diabetic rats as compared with those in the control groups (P<0.05, P<0.01) and insulin-treated rats (P<0.01). TGF-ß1 and Snail1 protein expressions could not be detected by immunohistochemical staining in the normal renal tissues, however, the strongly positive staining was observed in diabetic rat renal tubules. A time-dependent loss of TGF-ß1 and Snail1 expressions was detected in the kidney of insulin-treated rats. In diabetic rats tubular α-SMA positive staining was seen at the 16th week. E-cadherin expression was lost in diabetic rats. The expressions of TGF-ß1, Snail1 proteins and Snail1 mRNA were significantly up-regulated in diabetic rats, while down-regulated in insulin-treated rats (P<0.01). The expressions of E-cadherin protein and mRNA in the cortex were contrary to the expressions of TGF-ß1 and Snail1. Therefore, TGF-ß1 and Snail1 are possibly involved in the pathogenesis of TEMT in diabetic nephropathy rats.