HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis.
BACKGROUND
The klotho gene and its protein product are mainly expressed in the kidney. The klotho protein induces suppression of multiple aging-related phenotypes, and homozygous klotho gene mutant mice display various senescent morbidity. Chronic inhibition of nitric oxide synthase (NOS) induces arteriosclerosis, while HMG-CoA reductase inhibitors (statins) have pleiotropic vascular protective effects besides cholesterol lowering. Therefore, the present studies were performed to determine whether chronic NOS blockade would affect anti-ageing klotho protein expression. In addition, the effects of statins on klotho protein expression and arteriosclerosis in these rats were investigated.


METHODS
Forty-two rats were divided into 6 groups as follows: (1) control, (2) NOS blockade, (3) atorvastatin (10 mg/kg/day), (4) pitavastatin (3 mg/kg/day), (5) NOS blockade+atorvastatin, (6) NOS blockade+pitavastatin. To induce arteriosclerosis further, a cuff was placed around the left femoral artery in each rat. After 4 weeks observation, rats were killed and renal klotho expression and the level of arteriosclerosis were examined.


RESULTS
The rats of chronic NOS inhibition developed hypertension, while statin treatment did not affect blood pressure in the rats with or without NOS blockade. Despite statin treatment, plasma levels of lipids did not differ among 6 groups. Immunohistochemical staining revealed that klotho protein was localized in the renal tubules. Chronic NOS inhibition markedly reduced renal klotho protein expression, while treatment with atorvastatin or pitavastatin completely prevented the reduction of klotho expression induced by NOS inhibition. In addition, statin treatment significantly improved arteriosclerotic lesions induced by NOS inhibition and cuff placement.


CONCLUSIONS
Since statin treatment did not alter blood pressure or serum lipid profiles, a novel vascular protective effect of statins via enhancing anti-aging klotho protein expression is suggested.
Kuwahara
Noriko
N
Division of Hypertension and Nephrology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Sasaki
Susumu
S
Kobara
Miyuki
M
Nakata
Tetsuo
T
Tatsumi
Tetsuya
T
Irie
Hidekazu
H
Narumiya
Hiromichi
H
Hatta
Tsuguru
T
Takeda
Kazuo
K
Matsubara
Hiroaki
H
Hushiki
Shinji
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000517:prevention & control*; D000069059:Atorvastatin; D005966:Glucuronidase / Q000096:biosynthesis*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D000090265:Klotho Proteins; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D011758:Pyrroles / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011804:Quinolines; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D005966:Glucuronidase; D000090265:Klotho Proteins; C108475:pitavastatin