In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage.
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, 3.3x10(10) 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.
Mitani
Haruo
H
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Ishizaka
Nobukazu
N
Aizawa
Toru
T
Ohno
Minoru
M
Usui
Shin-ichi
S
Suzuki
Toru
T
Amaki
Toshihiro
T
Mori
Ichiro
I
Nakamura
Yasushi
Y
Sato
Misako
M
Nangaku
Masaomi
M
Hirata
Yasunobu
Y
Nagai
Ryozo
R
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003404:Creatinine / Q000652:urine; D015536:Down-Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005966:Glucuronidase; D006439:Hemodynamics / Q000187:drug effects; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D011507:Proteinuria / Q000139:chemically induced; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D008565:Membrane Proteins; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D003404:Creatinine; D005966:Glucuronidase; D000090265:Klotho Proteins