Abstract
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
Highlights
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing
While healthy TGR(mREN2)[27] rats had more positive alpha smooth muscle actin areas, marker of activation of hepatic stellate cells, in livers compared to respective wild type (WT) livers, the hepatic aSMA increased much less after CCl4 intoxication in TGR(mREN2)[27] rats compared to CCl4 intoxicated WT livers
This study shows for the first time that TGR(mREN2)[27] rats develop spontaneous fibrosis and portal hypertension, in addition to previously described steatosis and inflammation[12]
Summary
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)[27], leads to spontaneous development of NAFLD. TGR(mREN2)[27] is such a model, comprising the overexpression of mouse renin in transgenic rats, which leads to spontaneous development of NAFLD12, and underlining the pathogenic role of the renin-angiotensin system (RAS) in liver disease[11]. Overexpression of Ang II induces NAFLD in TGR(mREN2)[27] rats[12], a transgenic rat model with mouse renin overexpression To date in these model fibrosis and portal hypertension has not been described. After inducing additional liver injury (BDL, CCl4) in TGR(mREN2)[27] rats, we investigated whether these animals are more prone to fibrosis and portal hypertension
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