Vaněčková Ivana, Hojná Silvie, Vernerová Zdenka, Kadlecová Michaela, Rauchová Hana, Kompanowska-Jezierska Elzbieta, Vaňourková Zdeňka, Červenka Luděk, Zicha Josef
Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.
Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czechia.
Front Physiol. 2019 Sep 18;10:1145. doi: 10.3389/fphys.2019.01145. eCollection 2019.
Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ET) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ET blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial.
Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ET receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ET blockade for 50 weeks following NX.
At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ET receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ET blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ET blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment.
A diuretic added to the combined RAS and ET blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).
我们之前对杂合子Ren-2转基因大鼠（TGR）的研究表明，在肾素-血管紧张素系统（RAS）阻断基础上加用内皮素受体A（ET）阻断剂阿曲生坦进行长期治疗，对部分肾切除诱导的慢性肾脏病（CKD）模型具有肾脏保护作用。由于已知ET阻断会导致水肿，我们感兴趣的是在此治疗中加用利尿剂是否有益。
3月龄的TGR大鼠接受部分肾切除术（NX），并分为以下几组：（i）单独进行RAS阻断（血管紧张素受体阻断剂氯沙坦和血管紧张素转换酶抑制剂群多普利）；（ii）联合RAS（氯沙坦和群多普利）与ET受体阻断（阿曲生坦）；或（iii）在联合RAS + ET阻断基础上加用利尿剂（氢氯噻嗪），NX术后持续治疗50周。
研究结束时，所有治疗组的收缩压和心脏肥大均有相似程度的降低。RAS阻断基础上加用ET受体阻断可显著提高生存率，利尿剂治疗无进一步影响。然而，联合利尿剂与RAS + ET阻断可降低体重并具有有益的肾脏保护作用——减轻肾脏重量和肾脏损伤标志物。单独接受RAS阻断治疗的大鼠蛋白尿逐渐增加，而加用ET阻断可显著降低蛋白尿。在加用利尿剂治疗的大鼠中，整个实验过程中蛋白尿逐渐减少。
在Ren-2转基因大鼠部分肾切除诱导的CKD中，联合RAS和ET阻断基础上加用利尿剂具有晚期肾脏保护作用。该利尿剂改善了：肾功能（以蛋白尿和肌酐清除率评估）、肾脏形态（肾脏重量、肾小球体积）以及肾脏损伤的组织学标志物（肾小球硬化指数、肾小管间质损伤）。
