【摘 要】
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Intrarenal nitric oxide (NO) alteration plays an important role in the pathogenesis and progression of diabetic nephropathy (DN).Tetrahydrobiopterin (BH4) is reported to be the key catalytic factor fo
【机 构】
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Key Laboratory of New Drugs and Clinical Application, Xuzhou Medical College, Xuzhou 221002, Jiangsu
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Intrarenal nitric oxide (NO) alteration plays an important role in the pathogenesis and progression of diabetic nephropathy (DN).Tetrahydrobiopterin (BH4) is reported to be the key catalytic factor for NO production.Here,we tested the hypothesis that hyperglycemia modulates BH4 synthesis,which might contribute to the over-production of NO in high glucose (HG) cultured rat glomerular mesangial cells (MCs) and in the renal cortex of DN mice.In the in vitro study,the rat MC line HBZY-1 was cultured in DMEM with HG,BH4 levels and intra-and extra-cellular NO levels were determined.The activity,protein and mRNA of inducible nitric oxide synthase (iNOS) were also determined.In the in vivo study,BH4 levels,NO levels and iNOS in renal cortex of DN mice were determined.The results indicated that the production of BH4 was remarkably increased in HG cultured rat MCs.Inhibition of GTP cyclohydrolase Ⅰ,a key rate-limiting enzyme for BH4 biosynthesis,reversed the overproduction of NO and the up-regulation of iNOS induced by HG.Additionally,regulation of BH4 was mediated by the Jak2/Stat1 signal pathway,for inhibition of which significantly down-regulated the activity,protein and mRNA levels of GTP cyclohydrolase Ⅰ.Furthermore,the HG-induced increase in BH4 resulted in the proliferation and hypertrophy of MCs.Also,we found that inhibition of GTP cyclohydrolase Ⅰ of DN mice significantly decreased NO level,BH4 level and iNOS expression in renal cortex.Our results suggest that the inhibition of BH4 synthesis is an effective approach for decreasing NO overproduction in DN,which may hold great clinical significance for the prevention of DN.
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