生活習慣病の重積を基盤とするCKDを新たにMetabolic Kidney Diseaseと捉えた。近位尿細管におけるiNAMPTの意義について, iNAMPTはTGFβにより発現が低下することを明らかにした。iNAMPTプロモータ解析を行いこの発現調節の詳細を明らかにした。さらに糖尿病性腎症ではiNAMPTの発現低下によるSirt6の発現低下が組織線維化へ寄与する。NNMTの線維化に関わるメカニズムの検討を遂行した。NMMT過剰発現マウスの肝臓線維化は肝臓のメチオニン代謝反応の低下のためのメチル基の欠乏がCTGF遺伝子の発現をepigeneticに増加させて, 線維化が亢進したと考えられた。
We defined chronic kidney disease based on the diabetes, obesity, and hypertension as metabolic kidney disease and found the molecular mechanism. We delineated the pathological relevance of iNAMPT of proximal tubular cells. The expression of iNAMPT was reduced by TGFb in diabetic kidney disease. We also analyzed regulatory mechanism for the promoter activity of iNMPT genes. In diabetic kidney disease, iNAMPT expression was downregulated which contributed to the tissue fibrotic changes through the reduced expressions of Sirt6. We also investigated the role of NMMT in the pathogenesis of tissue fibrotic changes of both kidney and liver. NMMT-overexpressing mice exhibited prominent liver fibrosis but not renal fibrosis. Liver fibrosis was demonstrated to result from the decreased turnover of methionine metabolism, which lead to methyl-donor deficiency and epigenetic induction of CTGF gene in the liver.

研究種目 : 基盤研究(A)(一般)
研究期間 : 2014～2016
課題番号 : 26253053
研究分野 : 内分泌学, 腎臓病学