Angiotensin II receptor Neprilysin inhibitor (LCZ696) compared to Valsartan attenuates Hepatotoxicity in STZ-induced hyperglycemic rats

Abstract

Background and objectives: Although diabetic-induced hepatotoxicity is less common, it can be included in the list of target organ pathologies associated with diabetes. This study aimed to investigate the potential therapeutic role of sacubitril/valsartan (LCZ696) in modulating oxidative and inflammatory injuries and liver fibrosis in STZ-induced hyperglycemic rats in comparison to valsartan alone. Materials and Methods: Following the induction of diabetes using a single dose of streptozotocin (STZ), STZ-induced hyperglycemic animals were administered LCZ696 or valsartan for 6 weeks. Glucose, transaminases, lipid profile, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin - 6 (IL-6), were estimated using the obtained serum. Oxidative stress biomarkers including thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were measured in the liver homogenate. Additionally, the levels of TNF-α, IL-1β, IL-6, and nuclear factor - kappa β (NF-κB) levels were estimated in hepatic tissue. To assess the general histopathological changes, harvested liver tissue was treated with hematoxylin and eosin or Masson's trichrome staining to detect fibrosis. Results: STZ-induced hyperglycemic rats demonstrated high blood glucose, dyslipidemia, and significant elevation in hepatic transaminases, proinflammatory cytokines, NF-κB, lipid peroxidation, and hepatic fibrosis, with impairment in antioxidant enzymes. In STZ-induced hyperglycemic rats, the administration of LCZ696 ameliorated hyperglycemia, dyslipidemia, improved liver functions, and boosted antioxidants enzymes. Furthermore, LCZ696 therapy attenuated oxidation, inflammation, progression of liver injury, and hepatic fibrosis. LCZ696 was superior to valsartan in reducing AST, hepatic fibrosis, tissue IL-1β, TNF-α and NF-κB. In addition, compared with the valsartan group, LCZ696 significantly increased the antioxidant parameters such as GSH, SOD, CAT and GPx. Conclusion: Collectively, our data demonstrated that LCZ696 could suppress the progression of diabetes-induced hepatic fibrosis, correlating with reduced oxidative stress, hepatic inflammation and NF-κB compared with valsartan alone.

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction

“…In H 2 O 2 -treated HK-2 cells, LCZ696 decreased intracellular ROS and MitoSOX overproduction ( Fig 3C and 3D ). Similar actions of LCZ696 were also reflected in changes indicating subtotal nephrectomy [ 16 ], hepatotoxicity [ 20 ], and diabetic cardiomyopathy [ 21 ], which suggest that LCZ696 may be a potential scavenger of oxidative stress.…”

Redefining Iron Deficiency in Patients With Chronic Heart Failure

“…68 It might be hypothesized that potentiation of natriuretic peptides could stimulate erythropoietin and erythroid precursors through a cyclic guanosine monophosphate–dependent mechanism, 69,70 but potentiation of cyclic guanosine monophosphate with vericiguat acts to worsen anemia with HF, rather than alleviating it. 71 Instead, the pattern of changes in iron biomarkers with sacubitril/valsartan is consistent with an effect of neprilysin inhibition to mute inflammation, 72–74 thereby interfering with a major stimulus for the synthesis of hepcidin and ferritin. The suppression of serum levels of hepcidin and ferritin by neprilysin inhibition 68 would serve to ameliorate functional iron trapping, thus promoting iron use to achieve enhanced erythropoiesis.…”

Association of heart failure patients with and without sacubitril-valsartan use with incident cancer risk

“…Possible explantations might be related to the role of neprilysin, which is a critical player in the homeostasis of hepatic metabolism. 16,17 The observation indicates that the protective effect might be organ specific. Such plausible theories should be validated in the future studies.…”