Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

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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.

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We thank P. Mundel (Division of Nephrology, Massachusetts General Hospital and Harvard Medical School) and K. Asanuma (Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine) for providing cultured podocytes. We also thank S.J. Shankland and C. Campbell (Division of Nephrology, University of Washington) for providing culture PECs. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant 22790800).

Author information


  1. Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

    • Kazuhiro Hasegawa
    • , Shu Wakino
    • , Hitoshi Minakuchi
    • , Keiko Fujimura
    • , Kozi Hosoya
    • , Motoaki Komatsu
    • , Yuka Kaneko
    • , Takeshi Kanda
    • , Hirobumi Tokuyama
    • , Koichi Hayashi
    •  & Hiroshi Itoh
  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Petra Simic
    •  & Leonard Guarente
  3. Department of Internal Medicine, Shizuoka Red Cross Hospital, Shizuoka, Japan.

    • Yusuke Sakamaki
    •  & Eiji Kubota


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K. Hasegawa, S.W., L.G. and H.I. designed the experiments and the study. K. Hasegawa, P.S., Y.S. and E.K. collected data or performed experiments for the study. K. Hasegawa, S.W., P.S., H.M., K.F., K. Hosoya, M.K., Y.K., T.K., H.T., K. Hayashi, L.G. and H.I. analyzed the data and contributed to writing the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shu Wakino.

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