Pioglitazone enhances the antihypertensive and renoprotective effects of candesartan in Zucker obese rats fed a high-protein diet
Pioglitazone enhances the antihypertensive and renoprotective effects of candesartan in Zucker obese rats fed a high-protein diet
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DOI：
10.1291/hypres.31.745
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发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Kashihara, Naoki
中科院分区：
文献类型：
--
作者：
Namikoshi, Tamehachi;Tomita, Naruya;Kashihara, Naoki
代谢综合征是慢性肾脏疾病发展的危险因素。血管紧张素II 1型受体阻滞剂(ARB)和噻唑烷二酮(TZD)可能在代谢综合征中提供肾血管保护作用。然而，这两种药物联合使用对代谢综合征患者的效果仍有待确定。本研究的目的是评估ARB和TZD联合治疗对喂饲高蛋白饲料的Zucker肥胖大鼠的效果。Zucker肥胖大鼠给予高蛋白饲料(OHP；n=6)、含坎地沙坦的高蛋白饲料、ARB(OHP+C；n=6)或同时含有坎地沙坦和吡格列酮的高蛋白饲料(OHP+CP；n=6)。在整个研究过程中测量了收缩压和尿蛋白排泄量，并在12周时对肾脏组织学和免疫组织化学进行了评估。OHP大鼠出现高血压(157+/-4 mm Hg)和蛋白尿(178+/-44 mg/d)，坎地沙坦可显著改善这些情况(分别为143+/-3 mm Hg和84+/-25 mg/d)。Ploglitazone可增强坎地沙坦(121+/-3 mm Hg，16+/-8 mg/d)的降压和抗蛋白尿作用。组织学上，坎地沙坦可减轻OHP大鼠肾小球硬化、足细胞损伤、间质纤维化和单核/巨噬细胞向肾小管间质的浸润。吡格列酮可抑制OHP+C大鼠肾脏残余间质纤维化。我们的结果表明，吡格列酮增强了坎地沙坦对喂食高蛋白饮食的Zucker肥胖大鼠的降压、抗蛋白尿和可能的肾脏抗纤维化作用。ARB和TZD联合治疗对代谢综合征患者的肾损伤有保护作用。
The metabolic syndrome is a risk factor for the development of chronic kidney disease. Angiotensin II type 1 receptor blockers (ARBs) and thiazolidinediones (TZDs) provide renovascular protection, probably in the metabolic syndrome. However, the effect of both agents administered together in patients with metabolic syndrome remains to be determined. The aim of this study was to assess the effects of ARB plus TZD combination therapy in Zucker obese rats fed a high-protein diet, an animal model of metabolic syndrome and renal injury. Zucker obese rats were fed a high-protein diet (OHP; n=6), a high-protein diet containing candesartan, an ARB (OHP+C; n=6), or a high-protein diet containing both candesartan and pioglitazone (OHP+CP; n=6) for 12 weeks. Systolic blood pressure and urinary protein excretion were measured throughout the study, and renal histology and immunohistochemistry were assessed at 12 weeks. OHP rats developed hypertension (157 +/- 4 mmHg) and proteinuria (178 +/- 44 mg/d), and these conditions were significantly ameliorated by candesartan (to 143 +/- 3 mmHg and 84 +/- 25 mg/d, respectively). Ploglitazone enhanced the anti hypertensive and anti-proteinuric effects of candesartan (121 +/- 3 mmHg, 16 +/- 8 mg/d, respectively). Histologically, candesartan ameliorated glomerulosclerosis, podocyte injury, interstitial fibrosis and monocyte/macrophage infiltration into the tubulointerstitium in the kidneys of OHP rats. Pioglitazone abrogated residual interstitial fibrosis in the kidneys of OHP+C rats. Our results suggested that pioglitazone augmented the antihypertensive, anti-protein uric and possibly renal anti-fibrotic actions of candesartan in Zucker obese rats fed a high-protein diet. The combination therapy of ARB and TZD may protect against renal injury in patients with metabolic syndrome.