Abstract 1494: Hepatocyte Growth Factor Attenuates Angiotensin II Induced Renal Fibrosis through TGF-β1 Suppression by Anoikis of Myofibroblasts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kazuma Iekushi ◽  
Yoshiaki Taniyama ◽  
Junya Azuma ◽  
Fumihiro Sanada ◽  
Norio Dosaka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Renal Fibrosis ◽  
Type I ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Apoptosis ◽  
Hepatocyte Growth ◽  
Tgf Β1

Progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA positive myofibroblast which produce high amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Previous studies demonstrated that hepatocyte growth factor (HGF) improved kidney fibrosis in murine models, where direct molecular mechanisms of myofibroblasts have not yet been understood. We tested the hypothesis in vivo using cardiac specific overexpression HGF mice (HGF-Tg), which showed a significant increase in serum HGF concentration. Angiotensin II (Ang II) infusion significantly induced renal fibrosis in wild type mice, while renal fibrosis was significantly decreased in HGF-Tg mice accompanied by the degrease in interstitial myofibroblasts (P<0.05). Quantitative analysis demonstrated 1.69-folds induction of profibrtic cytokine, TGF-β1 mRNA in HGF-Tg with Ang II group compared with wild type with Ang II, and Collagen type I and IV mRNA expression was significantly decreased in HGF-Tg mice with Ang II. The antifibotic action of HGF-Tg mice was concordant with an increase in MMP-2, MMP-9 expression (1.32-fold, 1.33-fold vs wild type with Ang II infusion, P<0.05, respectively), and decreased TIMP-1, TIMP-2 expression (1.5-fold, 1.28-fold vs wild type with Ang II infusion, P<0.05, respectively). To further investigate the anti-fibrotic effect of HGF, we used cultured human mesangial cells (HMC). When HMC were treated with TGF-β1, cells underwent to phenotypic change similar to myofibroblasts, accompanied by the significant increase in c-Met/HGF receptor (P<0.05). Under such conditions, HGF induced anoikis-induced apoptosis of myofibroblasts. It also linked with FAK phosphorylation especially p-FAK (Y925) (P<0.05). When GM6001 (a broad-spectrum MMP inhibitor) was added with HGF, HGF-induced apptosis was significantly decreased. It was suggested that increased activities of MMPs underlie the major mechanism of HGF mediated anoikis induced apoptosis. The present study demonstrated that HGF elicited myofibroblast anoikis. Activation of MMPs in fibrotic kidney might be considered as a target to attenuate the progression of CKD.

scholarly journals Hepatocyte Growth Factor Inhibits Apoptosis by the Profibrotic Factor Angiotensin II via Extracellular Signal-regulated Kinase 1/2 in Endothelial Cells and Tissue Explants

2010 ◽  
Vol 21 (23) ◽  
pp. 4240-4250 ◽  
Author(s):  
Young H. Lee ◽  
Ana P. Marquez ◽  
Ognoon Mungunsukh ◽  
Regina M. Day
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Caspase 3 ◽  
Cytoplasmic Localization ◽  
Ang Ii ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Induced Apoptosis ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF), an endogenous tissue repair factor, attenuates apoptosis in many primary cell types, but the mechanism is not completely understood. Our laboratory demonstrated that angiotensin (Ang) II activates the intrinsic apoptotic pathway in primary endothelial cells (ECs) via reduction of the antiapoptotic protein Bcl-xL. Ang II decreased Bcl-xLmRNA half-life by reducing its binding to nucleolin, a protein that normally binds a 3′ AU-rich region and stabilizes Bcl-xLmRNA. We hypothesized HGF may block apoptosis induced by Ang II. We used primary EC and ex vivo cultures of rat lung tissue to investigate HGF inhibition of Ang II-induced apoptosis. Our data indicated HGF abrogated Ang II-induced apoptosis by inhibiting cytochrome c release, caspase-3 activation, and DNA fragmentation. RNA-immunoprecipitation experiments demonstrated that HGF stabilized Bcl-xLmRNA by increasing nucleolin binding to the 3′-untranslated region that was associated with cytoplasmic localization of nucleolin. Cytoplasmic localization of nucleolin and Bcl-xLmRNA stabilization required HGF activation of extracellular signal-regulated kinase (ERK)1/2, but not phosphatidylinositol 3-kinase. HGF also blocked Ang II-induced caspase-3 activation and lactate dehydrogenase release in tissue explants in an ERK-dependent manner.

Hepatocyte growth factor attenuates renal fibrosis through TGF-β1 suppression by apoptosis of myofibroblasts

2010 ◽  
pp. 1 ◽  
Author(s):  
Kazuma Iekushi ◽  
Yoshiaki Taniyama ◽  
Junya Azuma ◽  
Fumihiro Sanada ◽  
Hiroshi Kusunoki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Renal Fibrosis ◽  
Hepatocyte Growth ◽  
Tgf Β1

Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts

2005 ◽  
Vol 288 (5) ◽  
pp. H2131-H2139 ◽  
Author(s):  
Teruya Nakamura ◽  
Kunio Matsumoto ◽  
Shinya Mizuno ◽  
Yoshiki Sawa ◽  
Hikaru Matsuda ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Dilated Cardiomyopathy ◽  
Late Stage ◽  
Type I Collagen ◽  
Type I ◽  
Tissue Fibrosis ◽  
Therapeutic Benefits ◽  
Hepatocyte Growth ◽  
Tgf Β1

Structural remodeling of the myocardium, including myocyte hypertrophy, myocardial fibrosis, and dilatation, drives functional impairment in various forms of acquired and hereditary cardiomyopathy. Using cardiomyopathic Syrian hamsters with a genetic defect in δ-sarcoglycan, we investigated the potential involvement of hepatocyte growth factor (HGF) in the pathophysiology and therapeutics related to dilated cardiomyopathy, because HGF has previously been shown to be cytoprotective and to have benefits in acute heart injury. Late-stage TO-2 cardiomyopathic hamsters showed severe cardiac dysfunction and fibrosis, accompanied by increases in myocardial expression of transforming growth factor-β1 (TGF-β1), a growth factor responsible for tissue fibrosis. Conversely, HGF was downregulated in late-stage myopathic hearts. Treatment with recombinant human HGF for 3 wk suppressed cardiac fibrosis, accompanied by a decreased expression of TGF-β1 and type I collagen. Suppression of TGF-β1 and type I collagen by HGF was also shown in cultured cardiac myofibroblasts. Likewise, HGF suppressed myocardial hypertrophy, apoptosis in cardiomyocytes, and expression of atrial natriuretic polypeptide, a molecular marker of hypertrophy. Importantly, downregulation of the fibrogenic and hypertrophic genes by HGF treatment was associated with improved cardiac function. Thus the decrease in endogenous HGF levels may participate in the susceptibility of cardiac tissue to hypertrophy and fibrosis, and exogenous HGF led to therapeutic benefits in case of dilated cardiomyopathy in this model, even at the late-stage treatment.

Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis

2001 ◽  
Vol 280 (5) ◽  
pp. F777-F785 ◽  
Author(s):  
Guangjie Guo ◽  
Jeremiah Morrissey ◽  
Ruth McCracken ◽  
Timothy Tolley ◽  
Helen Liapis ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tumor Necrosis Factor ◽  
Renal Fibrosis ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Wild Type ◽  
Tnf Α ◽  
Factor Α ◽  
Tgf Β1 ◽  
Necrosis Factor

Angiotensin II upregulates tumor necrosis factor-α (TNF-α) in the rat kidney with unilateral ureteral obstruction (UUO). In a mouse model of UUO, we found that tubulointerstitial fibrosis is blunted when the TNF-α receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT1a or the TNF-α receptors TNFR1 and TNFR2 were knocked out to elucidate interactions between the two systems. The contribution of both systems to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout (KO) mice with an angiotensin-converting enzyme inhibitor, enalapril. The increased interstitial volume (Vvint) in the C57BI/6 wild-type mouse was decreased in the AT1a KO from 32.8 ± 4.0 to 21.0 ± 3.7% ( P < 0.005) or in the TNFR1/TNFR2 KO to 22.3 ± 2.1% ( P < 0.005). The Vvint of the TNFR1/TNFR2 KO was further decreased to 15.2 ± 3.7% ( P < 0.01) by enalapril compared with no treatment. The induction of TNF-α mRNA and transforming growth factor-β1 (TGF-β1) mRNA in the kidney with UUO was significantly blunted in the AT1a or TNFR1/TNFR2 KO mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO mouse with enalapril reduced both TNF-α and TGF-β1 mRNA and their proteins to near normal levels. Also, α-smooth muscle actin expression and myofibroblast proliferation were significantly inhibited in the AT1a or TNFR1/TNFR2 KO mice, and they were further inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating the angiotensin II or the TNF-α systems individually leads to partial blunting of fibrosis. Incapacitating both systems, by using a combination of genetic and pharmacological means, further inhibited interstitial fibrosis and tubule atrophy in obstructive nephropathy.

scholarly journals Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy

2012 ◽  
Vol 45 (12) ◽  
pp. 1150-1156 ◽  
Author(s):  
Ai-Lan Chen ◽  
Cai-Wen Ou ◽  
Zhao-Chu He ◽  
Qi-Cai Liu ◽  
Qi Dong ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cardiomyocyte Hypertrophy ◽  
Hepatocyte Growth

scholarly journals Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on β1-Integrin To Promote Normal Liver Development

2001 ◽  
Vol 21 (15) ◽  
pp. 5122-5131 ◽  
Author(s):  
Michael Weinstein ◽  
Satdarshan P. S. Monga ◽  
Ye Liu ◽  
Steven G. Brodie ◽  
Yi Tang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Type I ◽  
Β1 Integrin ◽  
Adhesive Properties ◽  
Regulatory Pathways ◽  
Smad Proteins ◽  
Hepatocyte Growth

ABSTRACT Smads serve as intracellular mediators of transforming growth factor β (TGF-β) signaling. After phosphorylation by activated type I TGF-β receptors, Smad proteins translocate to the nucleus, where they serve as transcription factors and increase or decrease expression of TGF-β target genes. Mice lacking one copy each ofSmad2 and Smad3 suffered midgestation lethality due to liver hypoplasia and anemia, suggesting essential dosage requirements of TGF-β signal components. This is likely due to abnormal adhesive properties of the mutant hepatocytes, which may result from a decrease in the level of the β1-integrin and abnormal processing and localization of E-cadherin. Culture of mutant livers in vitro revealed the existence of a parallel developmental pathway mediated by hepatocyte growth factor (HGF), which could rescue the mutant phenotype independent of Smad activation. These pathways merge at the β1-integrin, the level of which was increased by HGF in the cultured mutant livers. HGF treatment reversed the defects in cell proliferation and hepatic architecture in theSmad2 +/− ; Smad3 +/− livers.

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