Protective effects of limb remote ischemic per-conditioning on the heart injury induced by renal ischemic-reperfusion through the interaction of the apelin with the RAS/iNOS pathway

Abstract

Introduction: Remote ischemic conditioning upregulates endogenous protective pathways in response to ischemia-reperfusion injury. This study tested the hypothesis that limb remote ischemic per-conditioning (RIPerC) exerts cardioprotective effects via the renin-angiotensin system (RAS)/inducible nitric oxide synthase (iNOS)/apelin pathway. Methods: Renal ischemia-reperfusion injury (I/R) was induced by bilateral occlusion of the renal pellicles for 60 minutes, followed by 24 hours of reperfusion; sham-operated rats served as controls. RIPerC was induced by four cycles (5 minutes) of limb ischemia-reperfusion along with bilateral renal ischemia. The functional disturbance was evaluated by renal (BUN and creatinine) and cardiac (troponin I and lactate dehydrogenase) injury biomarkers. Results: Renal I/R injury increased renal and cardiac injury biomarkers that were reduced in the RIPerC group. Histopathological findings of the kidney and heart were also suggestive of amelioration injury-induced changes in the RIPerC group. Assessment of cardiac electrophysiology revealed that RIPerC ameliorated the decline in P wave duration without significantly affecting other cardiac electrophysiological changes. Further, renal I/R injury increased the plasma (322.40±34.01 IU/L), renal (8.27±1.10 mIU/mg of Protein), and cardiac (68.28±10.28 mIU/mg of Protein) angiotensin-converting enzyme (ACE) activities in association with elevations in the plasma and urine nitrite (25.47±2.01 & 16.62±3.05 μmol/L) and nitrate (15.47±1.33 & 5.01±0.96 μmol/L) levels; these changes were reversed by RIPerC. Further, renal ischemia-reperfusion injury significantly (P=0.047) decreased the renal (but not cardiac) apelin mRNA expression, while renal and cardiac ACE2 (P<0.05) and iNOS (P=0.043) mRNA expressions were significantly increased compared to the sham group; these effects were largely reversed by RIPerC. Conclusion: Our results indicated that RIPerC protects the heart against renal ischemia-reperfusion injury, likely via interaction of the apelin with the RAS/iNOS pathway.