Angiotensin type-2 (AT-2)-receptor activation reduces renal fibrosis in cyclosporine nephropathy: evidence for blood pressure independent effect.

Giovanna Castoldi,Gianpaolo Zerbini,Raffaella Carletti,Francesca Roma,Andrea Stella,Cira R.T Di Gioia

doi:10.1042/bsr20160278

Abstract

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 (P<0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (P<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 (P<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.

Highlights

Renal fibrosis represents a serious complication of chronic kidney diseases, leading to end-stage renal failure, independently on the aetiology of initial renal injury [1].The increase in collagen and extracellular matrix protein deposition in glomerular and tubulo-interstitial area, modulated by multiple molecular pathways, characterizes the progression of renal fibrosis [2,3].Generally, in the development of renal fibrosis it is recognized an initial increase in the synthesis of growth factors and cytokines by resident cells, accompanied by the influx of inflammatory cells, monocyte-macrophages, which further promotes the release of cytokines and matrix proteins [3]
Short-term protocol Effects of chronic short-term Compound 21 (C21) treatment on systolic blood pressure, glomerular filtration rate and urinary albumin excretion in CsA-treated rats Table 1 shows the effects of chronic short-term C21 administration on SBP, body weight (BW), kidney/BW, heart/BW, GFR and urinary albumin excretion in CsA-treated rats
The results of the present study demonstrate that chronic C21 treatment promotes nephroprotection in CsA nephropathy, by reducing renal fibrosis and inflammatory cell infiltration, in absence of blood pressure modifications

Summary

Introduction

The increase in collagen and extracellular matrix protein deposition in glomerular and tubulo-interstitial area, modulated by multiple molecular pathways, characterizes the progression of renal fibrosis [2,3]. In the development of renal fibrosis it is recognized an initial increase in the synthesis of growth factors and cytokines by resident cells, accompanied by the influx of inflammatory cells, monocyte-macrophages, which further promotes the release of cytokines and matrix proteins [3]. These alterations are followed by an excessive deposition of extracellular. Castoldi and others matrix proteins and by an abnormal process of matrix remodelling, which leads to the formation of renal scarring and to organ failure [4]

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