Kidney Disease Center of First Affiliated Hospital, and Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310003, China.
Department of Pharmacology, Gannan Healthcare Vocational College, Ganzhou 341000, China.
Sheng Li Xue Bao. 2022 Feb 25;74(1):125-133.
Captopril can have nephrotoxic effects, which are largely attributed to accumulated renin and "escaped" angiotensin II (Ang II). Here we test whether angiotensin converting enzyme-1 (ACE1) inhibition damages kidneys via alteration of renal afferent arteriolar responses to Ang II and inflammatory signaling. C57Bl/6 mice were given vehicle or captopril (60 mg/kg per day) for four weeks. Hypertension was obtained by minipump supplying Ang II (400 ng/kg per min) during the second 2 weeks. We assessed kidney histology by periodic acid-Schiff (PAS) and Masson staining, glomerular filtration rate (GFR) by FITC-labeled inulin clearance, and responses to Ang II assessed in afferent arterioles in vitro. Moreover, arteriolar HO and catalase, plasma renin were assayed by commercial kits, and mRNAs of renin receptor, transforming growth factor-β (TGF-β) and cyclooxygenase-2 (COX-2) in the renal cortex, mRNAs of angiotensin receptor-1 (ATR) and ATR in the preglomerular arterioles were detected by RT-qPCR. The results showed that, compared to vehicle, mice given captopril showed lowered blood pressure, reduced GFR, increased plasma renin, renal interstitial fibrosis and tubular epithelial vacuolar degeneration, increased expression of mRNAs of renal TGF-β and COX-2, decreased production of HO and increased catalase activity in preglomerular arterioles and enhanced afferent arteriolar Ang II contractions. The latter were blunted by incubation with HO. The mRNAs of renal microvascular ATR and ATR remained unaffected by captopril. Ang II-infused mice showed increased blood pressure and reduced afferent arteriolar Ang II responses. Administration of captopril to the Ang II-infused mice normalized blood pressure, but not arteriolar Ang II responses. We conclude that inhibition of ACE1 enhances renal microvascular reactivity to Ang II and may enhance important inflammatory pathways.
卡托普利可产生肾毒性作用，这主要归因于肾素的积累和“逃逸”的血管紧张素 II（Ang II）。在这里，我们测试血管紧张素转换酶 1（ACE1）抑制剂是否通过改变肾入球小动脉对 Ang II 和炎症信号的反应来损害肾脏。C57Bl/6 小鼠给予载体或卡托普利（60mg/kg/天）4 周。在第二 2 周期间，通过 Ang II（400ng/kg/min）的微量泵供应来获得高血压。通过 FITC 标记的菊粉清除率评估肾小球滤过率（GFR），并在体外评估 Ang II 对入球小动脉的反应。此外，通过商业试剂盒测定血管 HO 和过氧化氢酶、血浆肾素，通过 RT-qPCR 检测肾皮质中肾素受体、转化生长因子-β（TGF-β）和环氧化酶-2（COX-2）的 mRNA，肾小球前小动脉中血管紧张素受体-1（ATR）和 ATR 的 mRNA。结果表明，与载体相比，给予卡托普利的小鼠血压降低，GFR 降低，血浆肾素升高，肾间质纤维化和肾小管上皮空泡变性增加，肾 TGF-β 和 COX-2 的 mRNA 表达增加，HO 生成减少，肾小球前小动脉中过氧化氢酶活性增加，入球小动脉 Ang II 收缩增强。后者用 HO 孵育可被阻断。卡托普利对肾微血管 ATR 和 ATR 的 mRNA 无影响。给予 Ang II 的小鼠血压升高，入球小动脉 Ang II 反应降低。给予卡托普利可使 Ang II 输注小鼠的血压正常化，但不能使入球小动脉 Ang II 反应正常化。我们得出结论，ACE1 抑制剂增强了肾微血管对 Ang II 的反应性，并可能增强了重要的炎症途径。
