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Antiaging gene Klotho regulates endothelin-1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats

Wang, Yuhong; Sun, Zhongjie

doi: 10.1097/HJH.0000000000000233
ORIGINAL PAPERS: Genetic aspects

Objective: Klotho is an antiaging gene and is predominately expressed in kidneys. The endothelin system is critical in the regulation of kidney function. The objective of this study is to assess whether klotho affects the renal endothelin system in spontaneously hypertensive rats (SHRs).

Method: Four groups of male SHRs and one group of male Wistar–Kyoto (WKY) rats were used. In-vivo expression of klotho was achieved by AAV2 delivery of mouse klotho full-length cDNA (AAV.mKL). Four groups of SHRs were given (intravenously) AAV.mKL, AAV.LacZ, AAV.GFP, and phosphate-buffered saline, respectively. The WKY group was given phosphate-buffered saline and served as a control. At the end of week 12 after gene delivery, all animals were euthanized.

Results: Plasma endothelin-1 (ET-1) and renal ET-1 levels were increased in SHRs vs. WKY rats. In-vivo expression of klotho reversed the elevated ET-1 levels in SHRs. ETB receptor protein expression was decreased in both kidney cortex and medulla of SHRs. Interestingly, in-vivo expression of klotho abolished the downregulation of ETB protein expression in SHRs, suggesting that klotho regulates ETB receptor expression. Klotho gene delivery also eliminated the increase in the ratio of ETA/ETB in SHRs. Mitochondrial superoxide dismutase (Mn-SOD) protein expression was decreased in kidneys of SHRs, which was rescued by in-vivo expression of klotho.

Conclusion : Klotho gene delivery abolished the upregulation of ET-1 levels and the downregulation of ETB and Mn-SOD expression in kidneys of SHRs. These findings revealed a previously unidentified role of klotho in the regulation of the renal ET system and Mn-SOD in SHRs.

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Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Correspondence to Zhongjie Sun, MD, PhD, FAHA, Department of Physiology, BMSB 662A, College of Medicine, University of Oklahoma Health Sciences Center (OUHSC), 940 S.L. Young Blvd, Oklahoma City, OK 73104, USA. Tel: +1 405 271 2226x56237; fax: +1 405 271 3181; e-mail:

Abbreviations: Mn-SOD, mitochondrial superoxide dismutase; ET-1, endothelin-1; ETB, endothelin receptor subtype B; SHR, spontaneously hypertensive rat

Received 11 February, 2014

Revised 31 March, 2014

Accepted 31 March, 2014

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