尿細管-podocyte細胞連関の詳細を解明した。その結果db/dbマウスと近位尿細管特異的Sirt1欠損マウスの交配においてもアルブミン尿の発症は抑制され, この仲介物質としてのNMNが尿細管から糸球体へと伝達されることを証明した。また近位尿細管Sirt1はボーマン嚢壁側上皮の分化に関わること, iNAMPTの発現を介し, 線維化に関わることを証明した。つぎに近位尿細管特異的dnRhoA過剰発現マウスは高脂肪食により引き起こされる腎組織のRhoキナーゼの活性化が抑制され, 尿蛋白, アルブミン尿の正常化, 尿細管障害のマーカーの正常化, 細胞周期因子p27の発現調節を介する尿細管細胞増殖抑制が認められた。
We examined our hypothesis of tubule-podocyte communication by using proximal tubules (PT)-specific gene engineered mice. PT-specific Sirt1 deficient mice were crossed with db/db mice, which exhibited aggravated albuminuria. NMN, putative mediator of this interplay, was demonstrated to flow from PT to podocytes by photosensitive labelling. We also demonstrated that Sirt1 in PT have a role in the differentiation of parietal epithelial cells and in renal fibrosis by the regulation of iNAMPT. Proximal tubules specific dominant negative RhoA transgenic mice exhibited a decrease Rho/Rho kinase activation by high fat diet, which resulted in the decrease in albuminuria, tubular damages, and the proliferation and hypertrophy of PT cells. The downregulation of cell cycle regulator, p27 contributed to this change. These results suggested PT damage affects glomerular damages, which represent tubule-podocyte communication in diabetic nephropathy and obesity-induced glomerulopathy.

研究種目 : 基盤研究(B)(一般)
研究期間 : 2013～2015
課題番号 : 25293197
研究分野 : 腎臓病学, 内分泌代謝病学