Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function

Kazuhiro Hasegawa, Shu Wakino, Kyoko Yoshioka, Satoru Tatematsu, Yoshikazu Hara, Hitoshi Minakuchi, Keiko Sueyasu, Naoki Washida, Hirobumi Tokuyama, Maty Tzukerman, Karl Skorecki, Koichi Hayashi, Hiroshi Itoh

Research output: Contribution to journalArticle

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Abstract

Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.

Original languageEnglish
Pages (from-to)13045-13056
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number17
DOIs
Publication statusPublished - 2010 Apr 23

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Peroxisomes
Acute Kidney Injury
Cisplatin
Kidney
Transgenic Mice
Mitochondria
Sodium-Phosphate Cotransporter Proteins
Cells
Apoptosis
Proximal Kidney Tubule
Metabolism
NAD
Catalase
Restoration
Cultured Cells
Up-Regulation
Recovery
Cell Line
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. / Hasegawa, Kazuhiro; Wakino, Shu; Yoshioka, Kyoko; Tatematsu, Satoru; Hara, Yoshikazu; Minakuchi, Hitoshi; Sueyasu, Keiko; Washida, Naoki; Tokuyama, Hirobumi; Tzukerman, Maty; Skorecki, Karl; Hayashi, Koichi; Itoh, Hiroshi.

In: Journal of Biological Chemistry, Vol. 285, No. 17, 23.04.2010, p. 13045-13056.

Research output: Contribution to journalArticle

Hasegawa, Kazuhiro ; Wakino, Shu ; Yoshioka, Kyoko ; Tatematsu, Satoru ; Hara, Yoshikazu ; Minakuchi, Hitoshi ; Sueyasu, Keiko ; Washida, Naoki ; Tokuyama, Hirobumi ; Tzukerman, Maty ; Skorecki, Karl ; Hayashi, Koichi ; Itoh, Hiroshi. / Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 17. pp. 13045-13056.
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