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

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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 17 Pg. 13045-56 (Apr 23 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20139070 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Reactive Oxygen Species
• Slc34a1 protein, mouse
• Sodium-Phosphate Cotransporter Proteins, Type IIa
• Catalase
• Sirt1 protein, mouse
• Sirtuin 1
• Cisplatin

Topics

• Acute Disease
• Animals
• Antineoplastic Agents (adverse effects, pharmacology)
• Apoptosis (drug effects, genetics)
• Catalase (biosynthesis, genetics)
• Cell Line
• Cisplatin (adverse effects, pharmacology)
• Kidney Diseases (chemically induced, genetics, metabolism, therapy)
• Kidney Tubules, Proximal (injuries, metabolism, pathology)
• Longevity (drug effects, genetics)
• Male
• Mice
• Mice, Transgenic
• Mitochondria (genetics, metabolism)
• Organ Specificity
• Peroxisomes (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Sirtuin 1 (biosynthesis, genetics)
• Sodium-Phosphate Cotransporter Proteins, Type IIa (biosynthesis, genetics)
• Up-Regulation (drug effects, genetics)