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ToxSci Advance Access originally published online on June 24, 2009
Toxicological Sciences 2009 111(1):109-119; doi:10.1093/toxsci/kfp134
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Published by Oxford University Press 2009.

Effects of Nitric Oxide and Antioxidants on Advanced Glycation End Products-Induced Hypertrophic Growth in Human Renal Tubular Cells

Jau-Shyang Huang*,1, Lea-Yea Chuang{dagger}, Jinn-Yuh Guh{ddagger} and Yann-Jia Huang*

* Department of Biological Science and Technology, Chung Hwa University of Medical Technology, 717 Tainan {dagger} Department of Biochemistry {ddagger} Internal Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan, ROC

1 To whom correspondence should be addressed at Department of Biological Science and Technology, Chung Hwa University of Medical Technology, 89, Wen-Hwa 1st St. Jen-Te Hsiang, Tainan Hsien, 717 Taiwan, ROC. Fax: (886) 6-2675047. E-mail: jaushyang12{at}hotmail.com.

Received April 1, 2009; accepted June 10, 2009


  Abstract

The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in diabetic nephropathy (DN). Reactive oxygen species and nitric oxide (NO) were involved in the progression of DN. In this study, the molecular mechanisms of NO and antioxidants responsible for inhibition of AGE-induced renal tubular hypertrophy were examined. We found that AGE (but not nonglycated bovine serum albumin) significantly suppressed the NO/cGMP/PKG signaling in human renal proximal tubular cells. NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and antioxidants N-acetylcysteine (NAC)/taurine treatments significantly attenuated AGE-inhibited NO production, cGMP synthesis, and inducible NO synthase/cGMP-dependent protein kinase (PKG) activation. Moreover, AGE-induced extracellular signal-regulated kinase/c-Jun N-terminal kinase/p38 mitogen-activated protein kinase activation was markedly blocked by antireceptor for AGE (RAGE), SNAP, SNP, NAC, and taurine. The abilities of NO and antioxidants to inhibit AGE/RAGE–induced hypertrophic growth were verified by the observation that SNAP, SNP, NAC, and taurine inhibited fibronectin, p21Waf1/Cip1, and RAGE expression. Therefore, antioxidants significantly attenuated AGE/RAGE-enhanced cellular hypertrophy partly through induction of the NO/cGMP/PKG signaling.

Key Words: nitric oxide; antioxidant; advanced glycation end products; hypertrophy; renal proximal tubular cells.


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