NAD依存性脱アセチル化酵素Sirt1は, 通常は近位尿細管と足細胞(ポドサイト)の双方に発現するが, 糖尿病では, まず近位尿細管Sirt1が低下し, その結果Sirt1由来のニコチン酸代謝産物のNMNの分泌が減少した。NMNの減少で足細胞Sirt1も低下し, Epigenetic制御で本来足細胞に発現していないtight junctionの構成分子のClaudin1の発現が上昇し, 足細胞の癒合を引き起こし, 蛋白尿が出現する事を報告した(長谷川一宏, Nature Medicine 2013)。これらはTgマウスで増悪し, CKOマウスで増悪を認めた。
The protective role of Sirt1 in renal damage was investigated. Sirt1 in proximal tubules (PT) was downregulated before albuminuria occurred in streptozotocin-induced or obese-type (db/db) diabetes mellitus (DM) mice. PT-specific Sirt1 transgenic (TG) and knockout (KO) mice showed prevention and aggravation of glomerular changes in DM, respectively, and non-diabetic KO mice already exhibited albuminuria, suggesting that Sirt1 in PT affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein claudin-1 by Sirt1-mediated epigenetic regulation in podocytes contributed to albuminuria. We also demonstrated retrograde interplay from PT to glomeruli through NMN from conditioned medium, measurement of the auto-fluorescence of photoactivatable NMN, and injection of fluorescently labeled NMN. Sirt1 in PT protects against albuminuria in DM through maintaining NMN levels around glomeruli and controlling podocyte function.
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