Protective effect of valsartan alone and in combination with neprilysin inhibitor (valsartan + sacubitril) against hepatic ischemia-reperfusion injury: targeting angiotensin II receptor-neprilysin and modulating SMAD-4/NF-κβ/JNK pathways in rats.

Abstract

Ischemia-reperfusion injury (IRI) is a common pathogenic situation that arises throughout all liver surgeries, including liver transplants. We aimed to compare the preventive effects of valsartan (VST) against valsartan + sacubitril (LCZ696) on hepatic injury caused by IRI. A total of thirty-six male Westar albino rats were split into six groups randomly: sham, IRI, VST + IRI, LCZ696 + IRI, VST, and LCZ696. The medicines were given orally for 10 days in a row. Hepatic tissues and blood were examined through histopathological imaging and immunohistochemical detection of hepatic SMAD-4 protein expression plus serum aminotransferase (ALT, AST) and gamma-glutamyl transferase (GGT) levels. Angiotensin II, aldosterone, and plasma renin activity were evaluated in rat serum. Liver tissue homogenate was utilized to assess reduced glutathione (GSH), myeloperoxidase (MPO), malondialdehyde (MDA), and total nitric oxide (NOx) levels. Pro-inflammatory indicators, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), moreover with apoptosis indicators, BCL2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and galactine-9 (GAL9) proteins plus caspase-3, were measured in hepatic tissue homogenate. Hepatic endothelin-1 and neprilysin activity were evaluated. Western blot was done for c-Jun N-terminal kinase (JNK-7) plus nuclear factor-kappa B (NF-κβ) expressions. The study revealed that VST and LCZ696 pretreatment showed significant restoration of liver injury, correction of oxidative profile, and inhibition in the angiotensin II receptor-neprilysin pathway. Inflammatory mediators and apoptosis were significantly inhibited. The expression of SMAD-4, JNK-7, and NF-κβ proteins was notably diminished. The improvement in hepatic architecture supports these histopathological results. In conclusion, LCZ696 possesses a potentially significant protective effect against liver IRI superior to VST alone.