Advanced glycation end products-mediated hypertrophy is negatively regulated by tetrahydrobiopterin in renal tubular cells.
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 (BH(4)) and nitric oxide (NO) bioavailability may contribute to the aggravation of DN. The present study aims to explore any possible beneficial effect of exogenous BH(4) in alleviating the AGE-induced renal tubular hypertrophy in DN. Thus, renal tubular cells were treated with BH(4), BH(2), 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 BH(4)/BH(2) and sepiapterin treatments attenuated AGE-inhibited the iNOS/NO/GTPCH I protein synthesis. Moreover, BH(4) and BH(2) significantly reversed AGE-enhanced the JAK2-STAT1/STAT3 activation. The abilities of BH(4) and BH(2) to inhibit AGE-induced renal cellular hypertrophy were verified by the observation that BH(4) and BH(2) inhibited hypertrophic growth and the protein synthesis of p27(Kip1) and α-SMA. These findings indicate for the first time that exogenous BH(4) and BH(2) attenuate AGE-induced hypertrophic effect at least partly by increasing the iNOS/GTPCH I synthesis and NO generation in renal tubular cells.
Department of Dermatology, Chi Mei Medical Center, Tainan, Taiwan, ROC.
Yi-Chen
YC
Liao
Ying-Ho
YH
Lee
Lea-Yea
LY
Chuang
Jinn-Yuh
JY
Guh
Ming-Der
MD
Shi
Jau-Shyang
JS
Huang
D000199:Actins / Q000235:genetics / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D049108:Cell Enlargement; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D017127:Glycation End Products, Advanced / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011622:Pterins / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013400:Sugar Acids / Q000494:pharmacology
C017182:5-dehydro-3-deoxy-D-arabino-heptulosonic acid-7-phosphate; C541116:ACTA2 protein, human; D000199:Actins; C436291:CDKN1B protein, human; D017127:Glycation End Products, Advanced; D011622:Pterins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013400:Sugar Acids; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001708:Biopterins; D009569:Nitric Oxide; C017226:7,8-dihydrobiopterin; C016727:sepiapterin; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D006136:GTP Cyclohydrolase; C003402:sapropterin