HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells.
OBJECTIVE
Klotho is thought to play a critical role in the development of age-related disorders including arteriosclerosis. Statins may exert vascular protective effects, independent of the lowering of plasma cholesterol levels. We investigated the impact of statins on mRNA expression of the age-suppressor gene, klotho in mIMCD3 cells.


RESULTS
Klotho mRNA levels were evaluated with real-time RT-PCR. Atorvastatin and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner. This stimulatory effect was abolished by the addition of mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment, stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes. Furthermore, pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels. RhoA activity was further evaluated by detection of its translocation. Angiotensin II activated RhoA, whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II.


CONCLUSIONS
Statins inactivate the RhoA pathway, resulting in over-expression of klotho mRNA, which may contribute to the novel pleiotropic effects of statins towards vascular protection.
Department of Hypertension and Nephrology, Kyoto Prefectural University School of Medicine, 465 Kajii-cho Kawaramachi Hirokoji, Kyoto 602-8566, Japan. naru1117@koto.kpu-m.ac.jp
Hiromichi
H
Narumiya
Susumu
S
Sasaki
Noriko
N
Kuwahara
Hidekazu
H
Irie
Tetsuro
T
Kusaba
Hisako
H
Kameyama
Keiichi
K
Tamagaki
Tsuguru
T
Hatta
Kazuo
K
Takeda
Hiroaki
H
Matsubara
D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000069059:Atorvastatin; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005966:Glucuronidase; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007684:Kidney Tubules / Q000378:metabolism*; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000577:Amides; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D011725:Pyridines; D011758:Pyrroles; D011804:Quinolines; D012333:RNA, Messenger; D000804:Angiotensin II; C108830:Y 27632; D000069059:Atorvastatin; D005966:Glucuronidase; D000090265:Klotho Proteins; D020742:rhoA GTP-Binding Protein; C108475:pitavastatin