| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
Thiazolidinediones (TZD) are anti-diabetic drugs, which improve insulin-resistance. Although they are quite effective in treating diabetics, TZD have serious side effects of Na-retention. To clarify the mechanism of Na-retention by TZD, we examined the effects of TZD of renal proximal functions. In isolated proximal tubules from rabbit, TZD markedly activated NBC1 activity, and enhanced the rate of HCO3 absorption within several minutes. These results were blocked by MEK inhibitor as well as by PPARγ antagonist. TZD also enhanced ERK phosphorylation in renal cortex.
In fibroblast cells from wild-type mice, TZD enhanced the activity of NHE1. This effect was also blocked by MEK inhibitor as well as by PPARγ antagonist. In fibroblast cells from PPARγ-KO mice, however, TZD enhanced the NHE1 activity only after adenovirus-mediated PPARγ gene transfer. When only the ligand-binding domain was introduced in KO cells, however, TZD did not activate the NHE1. These results indicate that TZD stimulates renal proximal absorption through PPARγ/ERK pathway.
We also showed that insulin stimulates renal proximal absorption via PI3-kinase. In addition, IRS-2, but not IRS-1, plays an essential role in insulin effects of proximal function. Since defects in IRS-1 are frequently reported in type 2 diabetics or obesity, IRS-1 independent stimulation of renal Na-retention may have an important role in pathogenesis of hypertension associated with insulin-resistance.
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