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Thesis
アンギオテンシンタイプ1受容体拮抗薬オルメサルタンのPPARγ2プロモータへの転写活性増加作用

金沢　健太¹⁾，井上　郁夫¹⁾，池田　正明²⁾，片山　茂裕^1)
1)埼玉医科大学　内科学内分泌・糖尿病内科部門　²⁾埼玉医科大学　内科学内分泌・生理学教室

医学博士　甲第1028号　平成17年6月23日 （埼玉医科大学）

Angiotensin Type 1 Receptor Blocker, Olmesartan Induce Peroxisome Proliferator-Activated Receptorγ mRNA Level Through Promoter of PPARγ2
Kenta Kanazawa¹⁾, Ikuo Inoue¹⁾, Masaaki Ikeda²⁾, Shigehiro Katayama¹⁾ (Division of Endocrinology and Diabetes, Department of Internal medicine¹⁾, Department of Phisiology²⁾, Saitama Medical University, Moroyama, Iruma-gun, Saitama 350-0495, Japan)

Background: Angiotensin type 1 receptor (AT₁R) blockers (ARBs) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator-activated receptor γ (PPAR γ) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARγ function by ARB, olmesartan.
Methods and Results: The ARB, olmesartan dose dependently (from 0 to 50 nmol/L) significantly enhanced in mRNA expression of PPARγ in human kidney cell, human renal proximal tubule cells (RPTEC), by method of quantitative real-time polymerase chain reaction (olmesartan:2.15±0.25-fold induction). In addition, in transcription reporter assays, olmesartan (from 0 to 10 μmol/L) induced transcriptional activity of promoter of PPARγ2 by 1.29±0.22-fold (P＜0.05) and induced the gene expression level of PPARγ2 by 2.52±0.69-fold(P＜0.05). More over, olmesartan, dose dependently, induced transcriptional activity of promoter of cellular retinol-binding protein II (CRBP II) which is known as one of the target genes of PPARγ. Olmesartan induced PPARγ mRNA level through promoter of PPARγ2, resulting in stimulateing the target gene of PPARγ.
Conclusions: The present study demonstrates that olmesartan induces PPARγ activity through promoter of PPARγ2, resulting in enhancing of target of PPARγ. Our results demonstrate new pleiotropic actions of olmesartan, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.
Keywords: Olmesartan, Angiotensin type 1 receptor (AT₁R) blocker(ARB), Peroxisome proliferator-activated receptorγ (PPARγ), Cellular retionol- binding protein II (CRBPII)