Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis
Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis
复制标题
血管紧张素II、内皮素-1和L型钙通道在肾小球、肾小管间质和血管周围纤维化发展中的作用
作者：
T. Seccia;C. Maniero;A. Belloni;D. Guidolin;P. Pothen;A. Pessina;G. Rossi
目的 纤维化是多种疾病（包括动脉高血压）肾损害的标志。因此，我们在严重血管紧张素 II 依赖性高血压模型中研究了血管紧张素 II、内皮素-1 和 L 型钙通道在肾小球、血管和肾小管间质纤维化发展中的作用。方法 五周龄 Ren-2 转基因大鼠（TGRen2）接受 4 周安慰剂、波生坦（100 mg/kg 体重）、厄贝沙坦（50 mg/kg 体重）、ETA 选择性内皮素受体拮抗剂 BMS-182874（BMS；52 mg/kg 体重）、厄贝沙坦（50 mg/kg 体重）加 BMS（52 mg/kg 体重）的组合。体重）和硝苯地平（30毫克/公斤体重）。结果 通过组织形态计量学在每个肾脏的四到六个切片中准确量化肾小球体积、肾小管间质纤维化、肾小球和血管周围纤维化。 BMS 降低了肾小球纤维化（P < 0.001），而波生坦（P < 0.001）和厄贝沙坦（P < 0.005）则减弱了肾小管间质纤维化。硝苯地平和 BMS 可减少血管周围纤维化。由于只有厄贝沙坦和厄贝沙坦加 BMS 可以降低血压（与安慰剂相比，P < 0.001），因此这些对纤维化的影响与血压无关。结论 血管紧张素 II 和 L 型钙通道分别选择性地调节肾小管间质和血管周围室的纤维化。通过拮抗所有三个区室中的 ET-1 受体来预防纤维化，支持了 ET-1 在肾纤维化发展中的主要作用。
Objective Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension. Methods Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight). Results Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P < 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P < 0.001) and irbesartan (P < 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P < 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure. Conclusion Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.
DOI：
10.1152/ajprenal.00315.2004
发表时间：
2005-04
期刊：
American journal of physiology. Renal physiology
影响因子：
--
作者：
D. Pollock;John M Jenkins;A. Cook;J. Imig;E. Inscho
通讯作者：
D. Pollock;John M Jenkins;A. Cook;J. Imig;E. Inscho
内皮素异肽在人肾小球系膜细胞中引起 Ca2 信号传导和胞质游离 [Ca2] 的振荡。
DOI：
10.1016/0167-4889(90)90091-q
发表时间：
1990
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Simonson,MS;Osanai,T;Dunn,MJ
通讯作者：
Dunn,MJ
内皮素通过 ETA 刺激系膜细胞中丝裂原激活蛋白激酶的活性。
DOI：
10.1681/asn.v541074
发表时间：
1994
期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
--
作者：
Wang,Y;Pouysségur,J;Dunn,MJ
通讯作者：
Dunn,MJ