Akihiro Sakuyama

Xanthine Oxidase Inhibitor, Febuxostat Ameliorates the High Salt Intake–Induced Cardiac Hypertrophy and Fibrosis in Dahl Salt-Sensitive Rats

BACKGROUND Xanthine oxidase (XO) is a source of reactive oxygen species production in the heart. However, pathophysiological role of XO has not been clarified in hypertensive heart disease. Thus, the present study examined the impacts of high salt (HS) intake and febuxostat (Fx), a XO inhibitor in Dahl salt-sensitive (Dahl-S) rats. METHODS Eight-week old, male Dahl-S rats were fed a normal salt diet (0.6% NaCl) or a HS diet (8% NaCl) for 8 weeks. A part of the rats fed the HS diet were simultaneously treated with Fx (3 mg/kg/day). RESULTS HS intake increased blood pressure and heart weight with cardiomyocyte hypertrophy and interstitial fibrosis in the left ventricle (LV), and Fx diminished them. HS increased the XO activity 4.7-fold and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity 1.5-fold, and Fx not only blocked the XO activity but also inhibited the HS-increased NADPH oxidase activity. HS increased the expression of XO, collagen, transforming growth factor-β1 (TGF-β1), angiotensin-converting enzyme, and angiotensin II type 1 receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the LV, and Fx reduced the expression and phosphorylation of these proteins except XO. CONCLUSIONS Fx ameliorates the HS intake-induced hypertension, LV hypertrophy, and fibrosis with decreasing the TGF-β1 expression and ERK phosphorylation in Dahl-S rats. Fx also down-regulates cardiac NADPH oxidase and renin-angiotensin system. The XO inhibition may be an effective therapy for hypertensive heart disease.

Pitavastatin Upregulates Nitric Oxide Synthases in the Kidney of Spontaneously Hypertensive Rats and Wistar–Kyoto Rats

BACKGROUND Clinical trials show potent renoprotective effects of pitavastatin (PTV), although the precise mechanism for these renoprotective effects is not fully clarified. The aim of this study was to examine the antihypertensive and renoprotective effects of PTV, focusing on the nitric oxide (NO) system. METHODS Male, 6-week-old, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to receive vehicle or PTV (2 mg/kg bodyweight) for 8 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks. After 8 weeks, plasma biochemical parameters and renal histology were examined. NO synthase isoform (neuronal, nNOS; inducible, iNOS; and endothelial, eNOS) expression and eNOS phosphorylation were examined by western blotting. RESULTS PTV attenuated hypertension and albuminuria development in SHR. PTV decreased glomerular desmin expression and medullary interstitial fibrosis in SHR. PTV tended to increase plasma NO in both strains but significantly increased urinary NO excretion only in WKY. PTV significantly increased nNOS and eNOS expression, enhanced eNOS phosphorylation at serine1177, and inhibited eNOS phosphorylation at threonine495 in the kidney of both strains. CONCLUSIONS PTV treatment led to increased renal NOS expression and upregulated eNOS activity in both SHR and WKY. The antihypertensive and renoprotective effects of PTV may be related to upregulation of the NO system.

PS 07-05 ANGIOTENSIN II UPREGULATES CYTOCHROME-450 4A EXPRESSION IN RAT KIDNEY THROUGH TYPE 1 RECEPTOR

Objective: 20-hydroxyeicosatetraenoic acids (20-HETE) which is the major metabolites of arachidonic acid catalysed by cytochrome P-450 (CYP) 4A isoforms, is an important substance for the regulation of vascular tone and renal tubular function. Previous studies showed that angiotensin II (Ang II) stimulated the renal CYP activity and 20-HETE production in preglomerular arteries and renal tubules. However, the regulation of CYP4A expressions by Ang II in kidney has not been fully clarified. Design and Method: Experiments were performed on 8 week-old SD rats at Ang II at low dose (AL, 0.17 mg/kg/min, sc) and high dose (AH, 0.70 mg/kg/day, sc) by using osmotic mini pump, with or without angiotensin II type 1 (AT1) receptor blocker candesartan (CAN1, 1 mg/kg/day; CAN3, 3 mg/kg/day in drinking water) which were fed for 1 week. Systolic blood pressure (SBP) was measured by tail-cuff method. The expressions of CYP4A isoform in the kidney section were examined by immunoblot analysis. Results: Ang II significantly increased SBP in AH group, but not in AL group (control, 109 ± 2; AL, 115 ± 5; AH, 164 ± 8 mmHg). In the control group the CYP4A1, 4A2, and 4A8 proteins were highly expressed in the renal cortex, lowly expressed in the inner strip of outer medulla, and barely detectable in the inner medulla. Ang II dose-dependently increased the all CYP4A isoform expressions in the renal cortex and the inner strip of outer medulla (CYP4A1, 24% and 222%; CYP4A2, by 51% and 258%; CYP4A8, by 52% and 550% at high dose group). Candesartan treatment alone did not affect the CYP4A isoform expression, but it did dose-dependently inhibit the Ang II-increased CYP4A expression. Conclusions: Ang II increases CYP4A isoform expressions in the kidney through AT1 receptor. The Ang II-unregulated CYP4A expressions may play an important role in hypertension and renal function.

No. 192 Effects of Exercise Training on Renal Function in Salt-Sensitive Hypertensive Rats

坂田 佳子(東北大学病院内部障害リハビリテーション科) 参加会議名:8th World Congress of the International Society of Physical and Rehabilitation Medicine 開 催 地:Cancun, Mexico 参 加 期 間:平成 26年 6月 1日~ 5日 発表演題名:Effects of Exercise Training on Renal Function in Salt-Sensitive Hypertensive Rats 発表の成果: 我々はこれまでに腎疾患モデル動物を用いて運動の腎障害に対する効果について検討を 重ね,いくつかのモデルにおいて運動の腎保護作用を明らかにしてきたが,今回は食塩 感受性高血圧モデルラットにおいても運動が腎保護作用を発揮することを明らかにした のでこれを報告した.腎疾患に対する包括的リハビリテーション,すなわち腎臓リハビ リテーションは,慢性腎臓病患者の運動耐容能や QOLを向上させるのみならず,腎障害 の進展を抑制し生命予後を改善する積極的な治療法として期待されるが,リハビリテー ションの分野としては新しい領域であり,十分に認知されているとは言えない.今回, 腎臓リハビリテーションの主体となる運動の腎保護作用の科学的根拠をリハビリテー ション領域の最高峰の学会の 1つである ISPRMにて発表したことにより,腎臓リハビリ テーションの有効性や可能性を世界にアピールすることができたと思われる.また,今 後の研究の発展の手掛かりを得ることもできた.