The molecular mechanism of increase of TGF-β expression in diabetic glomeruli

点击翻译按钮获取中文摘要

The aim of this study is to clarify the molecular mechanism of the increased TGF-β expression in diabetic glomeruli or mesangial cells under high glucose conditions. First, we examined the effects to troglitazone, a PPARγ agonist, or PKCβ inhibitor (LY333531) on the development of diabetic nephropathy using animal models of diabetics. In STZ-induced diabetic rat glomeruli, the content of DAG, the activities of PKC and ERK were increased compared to control rats. The expression of TGF-β fibronection was also increased, and these abnormalities were normalized by troglitazone treatment. The effect of LY333531 was evaluated using dBdB mice, a model for type2 diabetes. In the glomeruli of dBdB mice, the increased amounts of TGF-β, type4 collagen and fibronectin were observed, which were prevented by LY333531 treatment. LY333531 also prevented the mesangial expansion or the increase of urinary albumin excretion in dB/dB mice.We next examined the regulation of TGF-β expression in cultured rat mesangial cells. In the cells under high glucose condition or stimulated by mechanical stretching, in vitro model for glomerular hypertension seen in diabetes mellitus, ERK activity was increased. High glucose induced activation of ERK was inhibited by PKC inhibitors, whereas stretch-induced ERK activation of ERK was not inhibited by PKC inhibitors, but by tyrosine kinase inhibitor. Mechanical stretching also increased the expression of TGF-β and fibronectin, and these increase were inhibited by MEK inhibitor.These results indicated that the expression of TGF-β was increased via PKC-ERK-dependent mechanism in diabetic glomeruli. The increase of ERK activity in diabetic state might be the consequence of synergistic effect of high glucose itself and mechanical stretching produced by glomerular hypertension, lead to the overproduction of TGF-β and extracellular matrix proteins, and thus involve the development and progression of diabetic glomerulosclerosis.