Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70

• Published in: Nephrology, dialysis, transplantation Vol. 25; no. 1; pp. 60 - 68
• Main Authors: Sugiura, Hidekazu, Yoshida, Takumi, Mitobe, Michihiro, Yoshida, Satsuki, Shiohira, Shunji, Nitta, Kosaku, Tsuchiya, Ken
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2010
• Subjects: acute kidney injury; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Adenoviridae - genetics; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; apoptosis; Apoptosis - physiology; Biological and medical sciences; Cell Line; Disease Models, Animal; Emergency and intensive care: renal failure. Dialysis management; Glucuronidase - genetics; Glucuronidase - metabolism; HSP70; HSP70 Heat-Shock Proteins - metabolism; Humans; Intensive care medicine; ischaemia-reperfusion; Kidney Medulla - metabolism; Kidney Medulla - pathology; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Klotho; Male; Medical sciences; Mice; Mice, Inbred BALB C; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; RNA, Messenger - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; Transfection; Up-Regulation; apoptosis; acute kidney injury; HSP70; ischaemia-reperfusion; Klotho; Kidney disease; Urinary system disease; Hemodialysis; Cardiovascular disease; Extrarenal dialysis; Reperfusion; Ischemia; Renal failure; Apoptosis
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfp451

Background. High Klotho expression has been detected in the kidney, and since the results of a recent study suggested that Klotho induction mitigates ischaemic damage in the kidney, in the present study we explored the mechanism by which Klotho expression reduces renal ischaemia-reperfusion injury (IRI). Methods. Male mice were subjected to bilateral renal ischaemia for 30 min and reperfusion for 24 h, or to a sham operation. Both the IRI group and the sham group were intravenously injected with an adenovirus harbouring the mouse Klotho gene (ad-kl) before renal IRI. In addition, mIMCD3 cells induced to overexpress Klotho by transferring the Klotho gene with ad-kl were analysed by DNA microarray and real-time PCR. Renal expression of Klotho and several genes selected by DNA microarray were assessed by real-time PCR or Western blotting, and TUNEL staining was performed to assess apoptosis. Results. Prior administration of ad-kl to the mice resulted in robust induction of Klotho mRNA in the kidney and liver. Ad-kl transfer improved the plasma creatinine values and mitigated the histological damage and apoptosis induced by IRI. Expression of several genes was altered in mIMCD3 cells as a result of the change in Klotho expression, and expression of heat shock protein 70 (HSP70), in particular, was up-regulated in ad-kl mouse kidneys and HK2 cells. Conclusion. The results suggest that Klotho is involved in the pathophysiology of IRI. Klotho mitigates apoptosis in experimental ischaemic acute kidney injury via expression of HSP70.