Angiotensin II (AngII) plays an important role in renal damage by acting on hemodynamics, cell-growth, proliferation, and fibrosis, mainly by effects on the AngII type 1 (AT(1)) receptor. The AT(1) receptor activates several intracellular signaling molecules such as mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, but their role in AngII-mediated renal damage is not well characterized. We therefore investigated whether pharmacologic blockade of ERK and p38 could prevent renal damage in high-renin homozygous transgenic rats (Ren2), with the effects of an AT(1) receptor antagonist (AT(1)-RA) as a reference. Seven-week-old homozygous Ren2 rats were treated with low-dose AT(1)-RA candesartan, ERK inhibitor tyrphostin, or p38 inhibitor SB239063 for 4 weeks. Untreated Ren2 and SD rats served as controls. Blood pressure was measured at 7 and 11 weeks. At 11 weeks, plasma renin activity (PRA) and serum aldosterone were determined, and the animals were killed. Kidney sections were scored for glomerular and interstitial smooth muscle actin and glomerular desmin expression as early markers for renal damage. Mesangial matrix expansion was determined as a marker for structural damage. PRA and aldosterone levels were elevated in untreated Ren2 rats in comparison to SD controls. AT(1)-RA further increased PRA but decreased aldosterone. All parameters of renal damage were elevated in untreated Ren2 rats. Blood pressure was not elevated at week 7 in Ren2 and not affected by either treatment. Mild signs of hypertensive damage were found in untreated Ren2 rats. All interventions significantly diminished damage to glomerular epithelium and interstitium. In addition, AT(1) receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT(1)-RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage.

中文翻译：

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特异性 MAP 激酶阻断可防止纯合子 TGR(mRen2)27 大鼠的肾损伤。

血管紧张素 II (AngII) 通过作用于血液动力学、细胞生长、增殖和纤维化，主要通过对 AngII 1 型 (AT(1)) 受体的作用，在肾损伤中发挥重要作用。AT(1) 受体激活几种细胞内信号分子，如丝裂原活化蛋白激酶细胞外信号调节激酶 (ERK) 和 p38，但它们在 AngII 介导的肾损伤中的作用尚不清楚。因此，我们研究了 ERK 和 p38 的药理阻断是否可以防止高肾素纯合子转基因大鼠 (Ren2) 的肾损伤，并以 AT(1) 受体拮抗剂 (AT(1)-RA) 的作用作为参考。七周大的纯合子 Ren2 大鼠用低剂量 AT(1)-RA 坎地沙坦、ERK 抑制剂 tyrphostin 或 p38 抑制剂 SB239063 治疗 4 周。未处理的 Ren2 和 SD 大鼠作为对照。在第 7 周和第 11 周测量血压。在第 11 周时，测定血浆肾素活性 (PRA) 和血清醛固酮，并处死动物。对肾切片的肾小球和间质平滑肌肌动蛋白和肾小球结蛋白表达进行评分，作为肾损伤的早期标志物。系膜基质扩张被确定为结构损伤的标志。与 SD 对照组相比，未治疗的 Ren2 大鼠的 PRA 和醛固酮水平升高。AT(1)-RA 进一步增加 PRA 但降低醛固酮。未经治疗的 Ren2 大鼠的所有肾损伤参数均升高。Ren2 在第 7 周时血压没有升高，并且不受任何一种治疗的影响。在未经治疗的 Ren2 大鼠中发现了轻微的高血压损伤迹象。所有干预措施都显着减少了对肾小球上皮和间质的损害。此外，AT(1) 受体和p38 阻断减少系膜基质扩张。在纯合子 Ren2 大鼠中，肾损伤可通过非低血压剂量的 AT(1)-RA 和类似地通过阻断 ERK 或 p38 得到改善。这表明 ERK 和 p38 参与了 AngII 介导的肾损伤。