Efrati Shai, Berman Sylvia, Ilgiyeav Eduard, Averbukh Zhan, Weissgarten Joshua
Nephrology Division, Department of Nephrology, Assaf Harofeh Medical Center, Zerifin, Israel.
Nephron Exp Nephrol. 2007;106(4):e107-12. doi: 10.1159/000104834. Epub 2007 Jun 29.
BACKGROUND/AIM: The angiotensin II level is elevated in subjects genetically prone to develop hypertension, triggering renal hypercellularity, cytokine production, and matrix deposition. Angiotensin-converting enzyme inhibition and/or angiotensin II type 1 receptor blockade attenuate renal damage. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist possessing antihypertensive and anti-inflammatory properties, was demonstrated to provide better renal protection than angiotensin-converting enzyme inhibitors. We studied the effects of in vivo peroxisome proliferator-activated receptor gamma activation by rosiglitazone on angiotensin II synthesis, proliferation, and apoptosis of mesangial cells of spontaneously hypertensive rats versus normotensive Sprague-Dawley rats.
The animals consumed either a high-sodium diet (8% Na) or a normal-sodium diet (0.5% Na). Half of each group received rosiglitazone at 5 mg/kg/day. After 3 weeks, all rats were sacrificed and the mesangial cells isolated and cultured. Angiotensin II was assessed by radioimmunoassay, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and cell proliferation by [(3)H]thymidine incorporation.
Only the spontaneously hypertensive rats which consumed the high-sodium diet developed hypertension (185 +/- 6 mm Hg vs. basal 128 +/- 5 mm Hg; p = 0.0007) which was attenuated by rosiglitazone (to 126 +/- 4 mm Hg; p = 0.34). Angiotensin II synthesis, proliferation, and apoptosis were exaggerated in mesangial cell cultures from Sprague-Dawley rats and, more so, spontaneously hypertensive rats fed the high-sodium diet, but were inhibited in cultures from rosiglitazone-treated animals.
Peroxisome proliferator-activated receptor gamma activation, in addition to lowering blood pressure, suppresses angiotensin II synthesis and downregulates angiotensin-II-mediated proliferation and apoptosis of mesangial cells. In the context of hypertension-induced renal damage, this would mean that the renoprotective role of rosiglitazone extends beyond glycemic and lipidemic control.
背景/目的：在遗传易患高血压的受试者中，血管紧张素II水平升高，引发肾细胞增多、细胞因子产生和基质沉积。血管紧张素转换酶抑制和/或血管紧张素II 1型受体阻断可减轻肾损伤。罗格列酮是一种具有抗高血压和抗炎特性的过氧化物酶体增殖物激活受体γ激动剂，已证明其比血管紧张素转换酶抑制剂能提供更好的肾脏保护作用。我们研究了罗格列酮体内激活过氧化物酶体增殖物激活受体γ对自发性高血压大鼠与正常血压的斯普拉格-道利大鼠系膜细胞血管紧张素II合成、增殖和凋亡的影响。
动物分别食用高钠饮食（8%钠）或正常钠饮食（0.5%钠）。每组一半动物接受5mg/kg/天的罗格列酮。3周后，处死所有大鼠，分离并培养系膜细胞。通过放射免疫测定法评估血管紧张素II，通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法评估凋亡，通过[³H]胸腺嘧啶掺入法评估细胞增殖。
仅食用高钠饮食的自发性高血压大鼠出现高血压（185±6mmHg对比基础值128±5mmHg；p = 0.0007），罗格列酮可使其减轻（降至126±4mmHg；p = 0.34）。在喂食高钠饮食的斯普拉格-道利大鼠以及更明显的自发性高血压大鼠的系膜细胞培养物中，血管紧张素II合成、增殖和凋亡均增加，但在罗格列酮处理动物的培养物中受到抑制。
过氧化物酶体增殖物激活受体γ激活除了降低血压外，还抑制血管紧张素II合成，并下调血管紧张素II介导的系膜细胞增殖和凋亡。在高血压诱导的肾损伤背景下，这意味着罗格列酮的肾脏保护作用超出了血糖和血脂控制范围。
