aliskiren and Liver-Cirrhosis

Schistosomiasis mansoni is involved in hepatic fibrogenesis and portal hypertension. Previous studies proved that blockade of some components of the renin-angiotensin system (RAS) reduce liver fibrogenesis. However, the effects of inhibition of early stages of RAS pathway in schistosomal fibrosis have not been studied yet. Thus, the aim of this study was to compare the role of different antihypertensive drugs on hepatic fibrosis in murine schistosomiasis. BALB/c mice (n = 50) weighing 20g were subjected to inoculation of 50 cercariae and submitted to different treatments: aliskiren, 50 mg/kg (n = 10); bradykinin, 2 μg/kg (n = 5); losartan, 10 mg/kg (n = 10); lisinopril 10 mg/kg (n = 5) and control, proportional volume vehicle (n = 5); daily for 14 weeks. Six animals were not subjected to cercariae inoculation or any type of treatment. Ultrasound, histological, immunohistochemical and proteomic analyzes were performed to evaluate markers associated with hepatic fibrogenesis. The hepatic areas stained with Sirius red and thenumber of cells marked by α-SMA in animals treated with aliskiren, bradykinin, lisinopril and losartan were diminished when compared to control group, demonstrating reduced hepatic fibrosis after RAS blockade. These results were reinforced by ultrasonography analysis and protein expression of TGFβ. These findings demonstrated the effect of RAS inhibition on hepatic fibrosis in murine schistosomiasis, with the most evident results being observed in the losartan and aliskiren treated groups. The main mechanisms underlying this process appear to involve anti-fibrogenic activity through the inhibition of collagen and TGFβ synthesis.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bradykinin; Fumarates; Lisinopril; Liver; Liver Cirrhosis; Losartan; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type III; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Schistosomiasis mansoni; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Vasodilator Agents

Increased angiotensin II (Ang II) plays an important role in liver inflammation and fibrogenesis. Chronic administration of aliskiren, a newly developed direct renin inhibitor, decreases Ang II in the hypertensive patients and animals.. Our study aims to evaluate the possible protective effects of chronic administration of aliskiren in a chronic liver injury model.. C57BL6 mice were injected intraperitoneally with carbon tetrachloride (CCl(4)) to induce chronic liver injury. The injured mice were randomly assigned to aliskiren-treated (25 mg/kg per day for 2 weeks, the CCl(4) + Ali group) or untreated group (the CCl(4) group). Mice without CCl(4) and aliskiren administration served as the normal control.. In the CCl(4)-injured mice, aliskiren attenuated liver inflammation and fibrosis. The levels of hepatocyte apoptosis, lipid peroxidation production, the activation of hepatic stellate cells and Kupffer cells, hepatic expression of p47 phox, inflammatory mediators and profibrotic markers were reduced in the CCl(4) + Ali group. Furthermore, aliskiren decreased Ang II, activated the renal expression of renin, but down-regulated the hepatic expression of renin and renin receptor in the CCl(4)-injected mice.. Aliskiren attenuates chronic liver injury in the CCl(4)-treated mice by reducing Ang II. Direct renin inhibition may serve as a potential treatment for chronic liver injury.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury, Chronic; Drug Interactions; Fumarates; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Random Allocation; Renin