Advanced glycation end products-mediated hypertrophy is negatively regulated by tetrahydrobiopterin in renal tubular cells

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• 作者：Yi-Chen Liao^a ; ^b ; Ying-Ho Lee^b ; ^c ; Lea-Yea Chuang^d ; Jinn-Yuh Guh^e ; Ming-Der Shi^f ; Jau-Shyang Huang^b ; ^{jaushyang12@hotmail.com}
• 关键词：Advanced glycation end products ; GTP cyclohydrolase I ; Hypertrophy ; Inducible nitric oxide synthase ; Nitric oxide ; Tetrahydrobiopterin
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2012
• 期刊代码：109_03037207
• 类别：bio
• 出版时间：15 May, 2012
• 卷：355
• 期：1
• 页码：71-77
• 文件大小：716 K

摘要

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in DN. Elimination of tetrahydrobiopterin (BH₄) and nitric oxide (NO) bioavailability may contribute to the aggravation of DN. The present study aims to explore any possible beneficial effect of exogenous BH₄ in alleviating the AGE-induced renal tubular hypertrophy in DN. Thus, renal tubular cells were treated with BH₄, BH₂, sepiapterin, or DAHP in the presence of AGE. We found that AGE (but not non-glycated BSA) markedly reduced NO production and increased hypertrophy index in these cells. Exogenous BH₄/BH₂ and sepiapterin treatments attenuated AGE-inhibited the iNOS/NO/GTPCH I protein synthesis. Moreover, BH₄ and BH₂ significantly reversed AGE-enhanced the JAK2-STAT1/STAT3 activation. The abilities of BH₄ and BH₂ to inhibit AGE-induced renal cellular hypertrophy were verified by the observation that BH₄ and BH₂ inhibited hypertrophic growth and the protein synthesis of p27^Kip1 and 伪-SMA. These findings indicate for the first time that exogenous BH₄ and BH₂ attenuate AGE-induced hypertrophic effect at least partly by increasing the iNOS/GTPCH I synthesis and NO generation in renal tubular cells.