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Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension.

ABSTRACT: The matricellular protein secreted protein acidic and rich in cysteine (SPARC) modulates cell adhesion, proliferation, matrix deposition, and tissue remodeling. SPARC has been shown to regulate the expression of collagen type I and transforming growth factor-beta1 in mesangial cells and to be highly expressed during tubulointerstitial fibrosis in rat angiotensin (ANG) II infusion models. We hypothesized that SPARC is a downstream effector of ANG II and that loss of host SPARC function provides a protective effect on renal damage and fibrosis associated with ANG II hypertension. Our results revealed that cultured primary mesangial cells displayed a concentration-dependent increase in SPARC expression in response to ANG II. After a 14-day chronic infusion of ANG II, hypertensive SPARC-null mice exhibited significantly attenuated levels of urinary and renal indicators of oxidative stress and inflammation and decreased renal perivascular and tubulointerstitial fibrosis relative to wild-type hypertensive controls. Moreover, the observed renal protective changes in SPARC-null mice were found to be independent of blood pressure. These results identify SPARC as an effector of ANG II signaling and suggest an important role for SPARC in mediating ANG II-induced oxidative stress, inflammation, and fibrosis.

SUBMITTER: Socha MJ

PROVIDER: S-EPMC1988862 | biostudies-other | 2007 Oct

REPOSITORIES: biostudies-other

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Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension.

Socha Matthew J MJ Manhiani Marlina M Said Neveen N Imig John D JD Motamed Kouros K

The American journal of pathology 20070823 4

The matricellular protein secreted protein acidic and rich in cysteine (SPARC) modulates cell adhesion, proliferation, matrix deposition, and tissue remodeling. SPARC has been shown to regulate the expression of collagen type I and transforming growth factor-beta1 in mesangial cells and to be highly expressed during tubulointerstitial fibrosis in rat angiotensin (ANG) II infusion models. We hypothesized that SPARC is a downstream effector of ANG II and that loss of host SPARC function provides a ...[more]

PMID: 17717147

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Project description:IntroductionSecreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC.MethodsTwo in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC(+/+)) and knock-out (SPARC(-/-)) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by ?-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC(-/-) and SPARC(+/+) mice using Affymetrix Mouse Gene ST 1.0 array.ResultsSPARC expression was found induced in fibrotic livers of mouse and human. SPARC(-/-) mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC(-/-) mice when compared to SPARC(+/+) mice; in addition, MMP-2 expression was increased in SPARC(-/-) mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-?1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli.ConclusionsOverall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.

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Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension.

Publications

Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension.

Similar Datasets

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