POTENTIAL ROLE OF GLP-1 RECEPTOR AGONIST IN A RAT MODEL OF CARDIO-RENAL SYNDROME TYPE-3: EFFECTS ON OXIDATIVE, INFLAMMATORY AND INOS EXPRESSION AXIS

Abstract

Background: Acute renal and cardiac diseases are common encounters in hospitalized and non-hospitalized patients. Kidney and heart pathology are continuously interrelated. The impact of acute kidney injury (AKI) on the cardiac function is demonstrated in both preclinical and clinical studies and is termed cardio-renal syndrome type 3.Aim of the work: The aim of this work is to establish an animal model of cardio-renal syndrome type 3, and to study the effect of glucagon-like peptide-1 receptor (GLP-1R) agonist “liraglutide” on this condition.Materials and methods: Sixty male Wistar rats were used in this study and were divided into six groups (10 per group). Group 1: control, Group 2: low dose liraglutide-treated rats(L-lira). Group 3: high dose liraglutide-treated rats (H-lira). Group 4: Gentamicin (GM) treated rats. Group 5: low dose liraglutide- and GM-treated rats (L-lira-GM). Group 6: high dose liraglutide- and GM-treated rats (H-lira-GM). Liraglutide was given daily by subcutaneous injection for three weeks. GM was injected intraperitoneally (IP) starting from day 15 to day 21.Results: GM treatment was associated with histopathological injuries of both renal and cardiac tissues, in addition to significant elevation of renal biomarkers (serum urea and creatinine) as well as cardiac biomarkers (cardiac troponin I (TnI), creatine kinase (CK-MB) and lactate dehydrogenase (LDH). ECG showed prolongation of QRS complex, Q-T and Q-Tc interval, in addition to increased T wave voltage. There was significant increase in the relative weight of the right ventricle and the absolute and relative weights of left ventricles and the whole heart of the GM group. Moreover, GM injection resulted in a significant increase in oxidative and inflammatory markers (MDA, NO, IL-1beta, IL-6 and TNF-α) and diminished antioxidants GSH, SOD, and catalase, in the serum as well as in renal and cardiac tissues. GLP-1R agonist administration before GM injection normalized all the measured parameters only in the high dose group. Liraglutide evidently prevented upregulation of the inducible nitric oxide synthase (iNOS) gene expression in both renal and cardiac tissue of GM-treated animals.Conclusion: GM injected rats exhibited renal and cardiac structural and functional damage. The GLP-1R agonist, liraglutide protects both the kidney and the heart through antioxidant and anti-inflammatory effects. In addition, it downregulates the iNOS expression in renal and cardiac tissues, thus decreasing production of nitric oxide (NO).