Implication of endoplasmic reticulum stress and mitochondrial perturbations in remote liver injury after renal ischemia/reperfusion in rats: potential protective role of azilsartan.

Objectives: Distant liver injury is a complication of renal ischemia-reperfusion (I/R) injury, which imposes mortality and economic burden. This study aimed to elucidate the cross-talk of endoplasmic reticulum (ER) stress and mitochondrial perturbations in renal I/R-induced liver injury, and the potential hepatoprotective effect of azilsartan (AZL).Methods: Male albino Wister rats were pre-treated with AZL (3 mg/kg/day, PO) for 7 days then a bilateral renal I/R or sham procedure was performed. Activities of liver enzymes were assessed in plasma. The structure and ultra-structure of hepatocytes were assessed by light and electron microscopy. Markers of ER stress, mitochondrial biogenesis and apoptosis were analyzed in livers of rats.Results: Renal ischemic rats showed higher plasma levels of liver enzymes than sham-operated rats, coupled with histological and ultra-structural alterations in hepatocytes. Mechanistically, there was up-regulation of ER stress markers and suppression of mitochondrial biogenesis-related proteins and enhanced apoptosis in livers of renal ischemic rats. These abnormalities were almost abrogated by AZL pretreatment.Discussion: Our findings uncovered the involvement of mitochondrial perturbations, ER stress and apoptosis in liver injury following renal I/R, and suggested AZL as a preconditioning strategy to ameliorate remote liver injury in patients susceptible to renal I/R after adequate clinical testing.

The cardioprotective effects of secoisolariciresinol diglucoside (flaxseed lignan) against cafeteria diet-induced cardiac fibrosis and vascular injury in rats: an insight into apelin/AMPK/FOXO3a signaling pathways.

Introduction: Fast food is a major risk factor for atherosclerosis, a leading cause of morbidity and mortality in the Western world. Apelin, the endogenous adipokine, can protect against cardiovascular disease via activating its receptor, APJ. Concurrently, secoisolariciresinol diglucoside (SDG), a flaxseed lignan extract (FLE), showed a therapeutic impact on atherosclerosis. The current study aimed to examine the effect of SDG on cafeteria diet (CAFD)-induced vascular injury and cardiac fibrosis via tracking the involvement of the apelin/APJ pathway. Methods: Thirty male rats were allocated into control, FLE-, CAFD-, CAFD/FLE-, and CAFD/FLE/F13A-treated rats, where F13A is an APJ blocker. All treatments lasted for 12 weeks. Results and discussion: The CAFD-induced cardiovascular injury was evidenced by histological distortions, dyslipidemia, elevated atherogenic indices, cardiac troponin I, collagen percentage, glycogen content, and apoptotic markers. CAFD increased both the gene and protein expression levels of cardiac APJ, apelin, and FOXO3a, in addition to increasing endothelin-1, VCAM1, and plasminogen activator inhibitor-1 serum levels and upregulating cardiac MMP-9 gene expression. Moreover, CAFD reduced serum paraoxonase 1 and nitric oxide levels, cardiac AMPK, and nuclear Nrf2 expression. FLE attenuated CAFD-induced cardiovascular injury. Such effect was reduced in rats receiving the APJ blocker, implicating the involvement of apelin/APJ in FLE protective mechanisms. Conclusion: FLE supplementation abrogated CAFD-induced cardiac injury and endothelial dysfunction in an apelin/APJ-dependent manner.