Castoldi Giovanna, di Gioia Cira R T, Carletti Raffaella, Roma Francesca, Zerbini Gianpaolo, Stella Andrea
Clinica Nefrologica, Ospedale San Gerardo di Monza, Dipartimento di Medicina e Chirugia, Università degli Studi di Milano-Bicocca, Monza 20900, Italy
Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Istituto di Anatomia Patologica, Sapienza Universita' di Roma, Roma 00161, Italy.
Biosci Rep. 2016 Nov 3;36(6). doi: 10.1042/BSR20160278. Print 2016 Dec.
Compound 21 (C21), selective agonist of angiotensin type-2 (AT-2) receptors, shows anti-inflammatory effects in experimental models of hypertension and nephroprotection in diabetes. The aim of the present study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague-Dawley rats. Cyclosporine-A (CsA; 15 mg/kg per day, intraperitoneal injection) and CsA plus C21 (0.3 mg/kg per day, intraperitoneal injection) were administered for 1 and 4 weeks. Control groups were left without any treatment. Blood pressure (plethysmographic method) and 24 h urinary albumin excretion were measured once a week. At the end of the experimental protocols, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and type IV collagen expression. After 1 and 4 weeks, the rats treated with CsA showed a significant increase (<0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (<0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared with the control rats. Treatment with C21 did not modify the CsA dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (<0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared with rats treated with cyclosporine. The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases.
化合物21（C21）是血管紧张素2型（AT-2）受体的选择性激动剂，在高血压实验模型中显示出抗炎作用，并对糖尿病具有肾脏保护作用。本研究的目的是评估C21对主要以肾小管间质纤维化为特征的环孢素肾病的影响。在实验期前10天及实验期间，对斯普拉格-道利大鼠给予低盐饮食。给予环孢素A（CsA；每天15mg/kg，腹腔注射）以及CsA加C21（每天0.3mg/kg，腹腔注射），持续1周和4周。对照组不做任何处理。每周测量一次血压（体积描记法）和24小时尿白蛋白排泄量。在实验方案结束时，切除肾脏以进行肾纤维化的组织形态计量分析以及炎症浸润和I型和IV型胶原表达的免疫组织化学评估。1周和4周后，与对照大鼠相比，接受CsA治疗的大鼠血压显著升高（<0.01），尿白蛋白排泄无显著变化，肾小球和肾小管间质纤维化及炎症浸润显著增加（<0.01）。C21治疗并未改变CsA依赖性的血压升高，该血压高于对照大鼠，但与接受环孢素治疗的大鼠相比，治疗4周后显著降低了（<0.01）肾小球和肾小管间质纤维化、I型胶原表达和巨噬细胞浸润。C21的给药对环孢素肾病显示出保护作用，减少了肾纤维化和巨噬细胞浸润。这些数据表明，C21可能抵消肾小管间质纤维化，而肾小管间质纤维化是肾脏疾病进展的最有力预测指标。
