Angiotensin-(1-7) reduces proteinuria and structural damage in renal tissue of salt-treated spontaneously hypertensive stroke-prone rats.

DOMINICI FP; GIANI JF; CAO G; MUÑOZ MC; TOBLLI JE

Ventura, CA, EEU

Conferencia; Gordon Research Conference on Angiotensin; 2010

INTRODUCTION: Chronic infllammation leads to renal fibrosis and reduces the glomerular levels of nephrin, one of the most important structural proteins of the renal ultrafiltration barrier. These alterations are important contributors to the development of proteinuria. In the current study we have evaluated the renal effects of chronic Ang-(1-7) treatment in salt-treated SHR/stroke-prone rats, an animal model of hypertension, nephropathy and insulin resistance.METHODS: 8 Male SHR/SP 1 month of age and their respective controls [Wistar-Kyoto (WKY)] were used for this study. Both groups of animals received NaCl 1,5% in the drinking water for 2 months. During the last 2 weeks of the study, half of the animals from each group (n =4 per group) received a daily intraperitoneal injection of Ang-(1-7) in a high dose ( 0.576 mg/kg)  [SHR/SP-Ang-(1-7)] and [WKY-Ang-(1-7)]. The rest of the animals received vehicle (saline) [SHR/SP-saline] y [WKY-saline]. Determinations of proteinuria and systolic blood pressure (SBP) were performed after 7 and 14 days of treatment with Ang-(1-7). By the end of the study renal interstitial fibrosis was determined by Masson’s trichrome staining. Besides, by means of inmunohistochemistry the levels of IL-6, TNF-a, NFkB and nephrin in renal glomeruli were determined. RESULTS. After 7 days of treatment with Ang-(1-7), proteinuria and SBP were significantly reduced in SHR/SP rats. This improvement was also detected after 14 days of treatment with Ang-(1-7). At the end of the study, SHR/SP-saline rats exhibited an important increased in renal fibrosis. This alteration was associated with an elevation of of IL-6, TNF-alpha and NFkB in renal cortex as detected by inmunohistochemisty. Ang-(1-7)-treatment induced a significant amelioration of renal fibrosis concomitant with a reduction of renal inmunostaining of IL-6, TNF-alpha and NFkB. These resullts were confirmed by detecting the analyzed pro-inflamatory molecules by inmunoblotting. Treatment with Ang-(1-7) did not produced changes at renal level in WKY rats. The SHR/SP-saline group exhibited a significant reduction in the content of nephrin in renal glomerulus.  Importantly, beneficial effects of Ang-(1-7) treatment in the kidney were associated with a marked restoration of nephrin levels in the renal glomerulus. Additionaly, Ang-(1-7) exerted beneficial metabolic effects by inducing a reduction of both circulating glucose and triglyceride levels in SHR/SP rats. CONCLUSIONS. The current study shows that chronic Ang-(1-7) administration to salt-treated SHR/SP produces both anti-inflammatory and anti-fibrotic actions at renal level as well as restoration of nephrin levels in renal cortex. These changes could explain, at least partially, the observed improvement in proteinuria and in SBP. Our observations suggest that chronic Ang-(1-7) treatment exerts a renoprotective effect together with an improvement of the metabolic profile in an animal model of hypertension, nephropathy and insulin resistance.