title: Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes.
abstract: Sirtuin 1 (Sirt1), a NAD(+)-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs 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 did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Petra
authors.initials: P
authors.lastname: Simic
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Minakuchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Fujimura
authors.forename: Kozi
authors.initials: K
authors.lastname: Hosoya
authors.forename: Motoaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.forename: Eiji
authors.initials: E
authors.lastname: Kubota
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Tokuyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000419:Albuminuria / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D062445:Claudin-1 / Q000235:genetics* / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008822:Mice, Transgenic; D008875:Middle Aged; D009537:Nicotinamide Mononucleotide / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D009537:Nicotinamide Mononucleotide; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1