Advanced glycation end products-mediated hypertrophy is negatively regulated by tetrahydrobiopterin in renal tubular cells
2012
Liao, Yi-Chen | Lee, Ying-Ho | Chuang, Lea-Yea | Guh, Jinn-Yuh | Shi, Ming-Der | Huang, Jau-Shyang
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 p27ᴷⁱᵖ¹ and α-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.
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