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(Hypertension. 2002;39:838.)
© 2002 American Heart Association, Inc.

Scientific Contributions

In Vivo klotho Gene Transfer Ameliorates Angiotensin II-Induced Renal Damage

Haruo Mitani; Nobukazu Ishizaka; Toru Aizawa; Minoru Ohno; Shin-ichi Usui; Toru Suzuki; Toshihiro Amaki; Ichiro Mori; Yasushi Nakamura; Misako Sato; Masaomi Nangaku; Yasunobu Hirata; Ryozo Nagai

From the Department of Cardiovascular Medicine (H.M., N.I., T.A, M.O., S.U., T.S., T.A., Y.H., RN), Department of Nephrology and Metabolic Diseases (M.N.), University of Tokyo Graduate School of Medicine, Tokyo, Japan; and Department of Pathology, Wakayama Medical University (I.M., Y.N., MS) Wakayama, Japan.

Correspondence to Nobukazu Ishizaka, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky{at}umin.ac.jp

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10¹⁰ plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.

Key Words: aging • angiotensin II • gene regulation • renal disease • hypertension, experimental

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