Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats
Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats
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DOI：
10.1111/j.1523-1755.2004.00476.x
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发表时间：
2004-03-01
影响因子：
19.6
通讯作者：
Abe, Y
中科院分区：
文献类型：
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作者：
Nishiyama, A;Yoshizumi, M;Abe, Y
背景丝裂原活化蛋白激酶（MAPK）级联是血管紧张素II（Ang II）诱导细胞生长和分化的重要细胞内介质。在此，我们研究了血管紧张素II 1型受体（AT（1））受体阻断剂对Dahl盐敏感（DS）大鼠肾损伤和MAPK活性的影响。DS大鼠维持高盐（H：8.0% NaCl，N = 8）或低盐（L：0.3% NaCl，N = 7）饮食或H +坎地沙坦酯（10 - 15 mg/kg/天，N = 8）。治疗4周后，测定尿蛋白排泄量（U蛋白V）、肾皮质胶原含量和肾小球损伤（通过半定量形态学分析评估）。用放射免疫法测定血浆和肾脏Ang II水平。通过Western-blotting分析来分析肾皮质组织中AT（1）和AT（2）受体的蛋白水平。采用Western blotting或体外激酶分析法检测细胞外信号调节激酶（ERK）1/2、c-Jun氨基末端激酶（JNK）、p38 MAPK和Big-MAPK-1（BMK 1）的活性。DS/H大鼠的平均血压（MBP）、尿蛋白V和肾皮质胶原含量均高于DS/L大鼠。在DS/H大鼠肾皮质组织中观察到ERK 1/2、JNK和BMK 1活性增加（分别约为6.3、4.5和2.5倍），而p38 MAPK活性无变化。DS/H大鼠血浆Ang II水平显著低于DS/L大鼠，而肾脏Ang II含量和AT 1受体蛋白水平与DS/L大鼠相似。坎地沙坦不改变MBP，但显著降低U蛋白V和胶原含量，并改善进行性硬化和增生性肾小球变化。此外，坎地沙坦可降低DS/H大鼠肾组织Ang II含量（从216 +/- 19降至46 +/- 3 fmol/mL）和ERK 1/2、JNK和BMK 1活性（分别为45%、60%和70%）。在DS高血压大鼠中，AT（1）受体阻断的某些肾脏保护作用伴随着肾内Ang II含量和MAPK活性的降低，这可能不是通过动脉压变化介导的。
Background. The mitogen-activated protein kinase (MAPK) cascade is an important intracellular mediator of angiotensin II (Ang II)-induced cell growth and differentiation. Here, we examined the effect of angiotensin II type 1 receptor (AT(1)) receptor blockade on renal injury and MAPK activity in Dahl salt-sensitive (DS) rats.Methods. DS rats were maintained on a high (H: 8.0% NaCl, N = 8) or low (L: 0.3% NaCl, N = 7) salt diet, or H + candesartan cilexetil (10 to 15 mg/kg/day, N = 8). Urinary protein excretion (UproteinV), renal cortical collagen content, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined after 4-week treatments. Plasma and kidney Ang II levels were measured by radioimmunoassay. Protein levels of AT(1) and AT(2) receptors in the renal cortical tissues were analyzed by Western-blotting analyses. MAPKs activities, including extracellular signal-regulated kinases (ERK) 1/2, c-Jun NH2-terminal kinases (JNK), p38 MAPK, and Big-MAPK-1 (BMK1), were measured by Western-blotting analyses or in vitro kinase assays.Results. DS/H rats showed higher mean blood pressure (MBP), UproteinV, and renal cortical collagen content than DS/L rats. Increased ERK1/2, JNK, and BMK1 activities were observed in renal cortical tissues of DS/H rats (approximately 6.3-, 4.5-, and 2.5-fold, respectively), whereas p38 MAPK activity was unchanged. Plasma Ang II levels were significantly reduced in DS/H rats compared with DS/L rats, whereas kidney Ang II contents and AT1 receptor protein levels were similar. Candesartan did not alter MBP, but significantly reduced UproteinV and collagen content, and ameliorated progressive sclerotic and proliferative glomerular changes. Furthermore, candesartan decreased renal tissue Ang II contents (from 216 +/- 19 to 46 +/- 3 fmol/mL) and ERK1/2, JNK, and BMK1 activities (45%, 60%, and 70%, respectively) in DS/H rats.Conclusion. In DS hypertensive rats, some of the renoprotective effects of AT(1) receptor blockade are accompanied by reductions in intrarenal Ang II contents and MAPK activity, which might not be mediated through arterial pressure changes.