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Título:
Angiotensin-(1-7) reduces proteinuria and structural damage in renal tissue of salt-treated spontaneously hypertensive stroke-prone rats.
Autor/es:
DOMINICI FP; GIANI JF; MUÑOZ MC; CAO G; TOBLLI JE
Lugar:
Ventura, California
Reunión:
Simposio; Gordon Research Conference on Angiotensin; 2010
Institución organizadora:
Gordon Research Conferences
Resumen:
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 Massons 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.