Atorvastatin upregulates nitric oxide synthases with Rho-kinase inhibition and Akt activation in the kidney of spontaneously hypertensive rats.
OBJECTIVE
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins reduce blood pressure and have beneficial effects in cardiovascular and kidney diseases. The present study examined the effect of chronic treatment with atorvastatin (ATV) on the expression of nitric oxide synthase (NOS) and the activity of Rho-kinase and Akt in the kidney of spontaneously hypertensive rats (SHRs).


METHODS
SHRs were treated with ATV for 8 weeks and the SBP was measured. The expressions of endothelial, neuronal and inducible NOS (eNOS, nNOS and iNOS, respectively) proteins in the kidney were examined by immunoblot analysis. The activity of eNOS, Rho-kinase and Akt in the kidney was examined by assessing the phosphorylation of eNOS, ezrin/radixin/moesin (ERM) and Akt, respectively.


RESULTS
ATV reduced the SBP without changing the plasma cholesterol levels. ATV increased eNOS expression in the cortex and medulla and nNOS expression in the medulla, whereas it did not affect iNOS expression. Although it upregulated eNOS expression in the kidney, ATV decreased the levels of phosphorylated eNOS in the cortex and did not affect the ratio of phosphorylated eNOS to total eNOS in the medulla. ATV also inhibited Rho-kinase activity and enhanced Akt activity in the kidney of SHRs.


CONCLUSIONS
ATV upregulates eNOS and nNOS expressions with Rho-kinase inhibition and Akt activation in the kidney of SHRs. The renal nitric oxide system, Rho-kinase and Akt may contribute to the antihypertensive and renoprotective effects of statins.
Ito
Daisuke
D
Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Ito
Osamu
O
Mori
Nobuyoshi
N
Muroya
Yoshikazu
Y
Cao
Peng-Yu
PY
Takashima
Kenta
K
Kanazawa
Masayuki
M
Kohzuki
Masahiro
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000069059:Atorvastatin; D001794:Blood Pressure; D006538:Heptanoic Acids / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000737:chemistry; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000959:Antihypertensive Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D009569:Nitric Oxide; D000069059:Atorvastatin; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases