Adenoviral <scp>CCN</scp>3/<scp>NOV</scp> gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis

Borkham-Kamphorst, Erawan; Huss, Sebastian; Leur, Eddy Van de; Haas, Ute; Weiskirchen, Ralf

doi:10.1111/j.1478-3231.2012.02837.x

Cited by 22 publications

(24 citation statements)

References 41 publications

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“…This hypothesis was reinforced by the fact that overexpression of NOV in vascular smooth muscle cells inhibited the angiotensin II profibrotic effects by down regulating both AT 1 R and CTGF expressions (Marchal PO et al, 2014 submitted manuscript). These observations are in line with previous data showing that the suppression of NOV enhanced expression of profibrotic marker proteins, such as α-smooth muscle actin, collagen type I, and CTGF in primary rat hepatic stellate cells [ 32 ]. In addition, overexpression of NOV reduced glomerulosclerosis and cortical accumulation of collagen type I in progressive glomerulonephritis [ 20 ].…”

Section: Discussionsupporting

confidence: 92%

“…In addition, the nature of the interactions in distinct physiopathological contexts can also govern the ability of NOV to interact with various partners providing contradictory results. Of note, recent studies showed that adenoviral NOV gene transfer failed to attenuate fibrogenesis in an in vivo model of experimental liver fibrosis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

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Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice

et al. 2015

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The main hallmark of chronic kidney disease (CKD) is excessive inflammation leading to interstitial tissue fibrosis. It has been recently reported that NOV/CCN3 could be involved in kidney damage but its role in the progression of nephropathies is poorly known. NOV/CCN3 is a secreted multifunctional protein belonging to the CCN family involved in different physiological and pathological processes such as angiogenesis, inflammation and cancers. The purpose of our study was to determine the role of NOV/CCN3 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After unilateral ureteral obstruction (UUO), renal histology and real-time PCR were performed in NOV/CCN3-/- and wild type mice. NOV/CCN3 mRNA expression was increased in the obstructed kidneys in the early stages of the obstructive nephropathy. Interestingly, plasmatic levels of NOV/CCN3 were strongly induced after 7 days of UUO and the injection of recombinant NOV/CCN3 protein in healthy mice significantly increased CCL2 mRNA levels. Furthermore, after 7 days of UUO NOV/CCN3-/- mice displayed reduced proinflammatory cytokines and adhesion markers expression leading to restricted accumulation of interstitial monocytes, in comparison with their wild type littermates. Consequently, in NOV/CCN3-/- mice interstitial renal fibrosis was blunted after 15 days of UUO. In agreement with our experimental data, NOV/CCN3 expression was highly increased in biopsies of patients with tubulointerstitial nephritis. Thus, the inhibition of NOV/CCN3 may represent a novel target for the progression of renal diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice

et al. 2015

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“…Reactive oxygen species (ROS) levels were measured as previously described 21. In brief, mouse hepatocytes were cultured on collagen‐coated glass slides.…”

Section: Methodsmentioning

confidence: 99%

Proapoptotic Effects of the Chemokine, CXCL 10 Are Mediated by the Noncognate Receptor TLR4 in Hepatocytes

Sahin

Borkham-Kamphorst

et al. 2013

Hepatology

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Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis in vivo. Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail in vitro. The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A-induced tissue injury in vivo, which was strongly associated with reduced liver cell apoptosis. In vitro, CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis in vivo. Conclusion: The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis. (HEPATOLOGY 2013;57:797-805)

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“…In our laboratory, we have extensively used this protocol in the past in rats in several experimental studies aiming to investigate special molecular and cellular aspects of hepatic fibrogenesis and to test novel antifibrotic concepts and drugs [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis

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Sauer-Lehnen

Weiskirchen

et al. 2015

JoVE

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In most vertebrates, the liver produces bile that is necessary to emulsify absorbed fats and enable the digestion of lipids in the small intestine as well as to excrete bilirubin and other metabolic products. In the liver, the experimental obstruction of the extrahepatic biliary system initiates a complex cascade of pathological events that leads to cholestasis and inflammation resulting in a strong fibrotic reaction originating from the periportal fields. Therefore, surgical ligation of the common bile duct has become the most commonly used model to induce obstructive cholestatic injury in rodents and to study the molecular and cellular events that underlie these pathophysiological mechanisms induced by inappropriate bile flow. In recent years, different surgical techniques have been described that either allow reconnection or reanastomosis after bile duct ligation (BDL), e.g., partial BDL, or other microsurgical methods for specific research questions. However, the most frequently used model is the complete obstruction of the common bile duct that induces a strong fibrotic response after 21 to 28 days. The mortality rate can be high due to infectious complications or technical inaccuracies. Here we provide a detailed surgical procedure for the BDL model in mice that induce a highly reproducible fibrotic response in accordance to the 3R rule for animal welfare postulated by Russel and Burch in 1959.

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Adenoviral CCN3/NOV gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis

Cited by 22 publications

References 41 publications

Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice

Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice

Proapoptotic Effects of the Chemokine, CXCL 10 Are Mediated by the Noncognate Receptor TLR4 in Hepatocytes

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis

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