Renal tubular sirt1 attenuates diabetic albuminuria by epigenetically suppressing claudin-1 overexpression in podocytes

Kazuhiro Hasegawa, Shu Wakino, Petra Simic, Yusuke Sakamaki, Hitoshi Minakuchi, Keiko Fujimura, Kozi Hosoya, Motoaki Komatsu, Yuka Kaneko, Takeshi Kanda, Eiji Kubota, Hirobumi Tokuyama, Koichi Hayashi, Leonard Guarente, Hiroshi Itoh

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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.

Original languageEnglish
Pages (from-to)1496-1504
Number of pages9
JournalNature medicine
Volume19
Issue number11
DOIs
Publication statusPublished - 2013 Nov

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hasegawa, K., Wakino, S., Simic, P., Sakamaki, Y., Minakuchi, H., Fujimura, K., Hosoya, K., Komatsu, M., Kaneko, Y., Kanda, T., Kubota, E., Tokuyama, H., Hayashi, K., Guarente, L., & Itoh, H. (2013). Renal tubular sirt1 attenuates diabetic albuminuria by epigenetically suppressing claudin-1 overexpression in podocytes. Nature medicine, 19(11), 1496-1504. https://doi.org/10.1038/nm.3363