The Potential Ameliorative Effect of Empagliflozin on Myocardium in Cardiorenal Syndrome 3 via Targeting Mitophagy and Mitochondrial Biogenesis in Adult Male Albino Rat Model: Biochemical, Histological and Immunohistochemical Study

Document Type : Original Article

Authors

1 Histology Department Faculty of Medicine Cairo University, Cairo, Egypt

2 Histology Department, Faculty of Medicine, Cairo University, Cairo, Egypt

Abstract

Background: Cardiorenal syndrome-3 (CRS3) represents the pathological link between kidneys and heart where acute kidney injury (AKI) causes serious cardiac abnormalities. Disrupted mitochondrial dynamics are the main contributor to CRS3. Mitophagy plays a protective role through reducing mitochondrial damage and oxidative-stress. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor, has therapeutic effects on cardiac and renal pathology with or without diabetes type-2 through anti-oxidative, anti-inflammatory &anti-apoptotic mechanisms. Aim of work: Evaluating EMPA probable reparative impact on the myocardium of adult male albino rat CRS3-model using biochemical, histological &immunohistochemical studies. Materials and Methods: Twenty-eight adult male albino rats (3months old, 200g weight) were divided into: control &experimental (subjected to AKI) groups. AKI-rats were subdivided equally into 3 subgroups, AKI, AKI/recovery &AKI/EMPA (received daily oral 20mg/kg EMPA 1week after renal surgery for 3weeks). Results: AKI induced a significant rise in serum urea, creatinine, cardiac TNF-α, H2O2 levels, P62, cytochrome-C area percentage, besides a non-significant increase in Mn-SOD level, mitophagy-PINK1/PARKIN &mitochondrial biogenesis-PGC1α gene expression, LC3B, sirtuin-3 area percentage &a significant decrease in ATP level. Myocardium showed darkly stained shrunken nuclei, disrupted transverse striations by H&E stain and minimal collagen deposition by Masson’s trichrome. AKI/recovery recorded further reduction in ATP, Mn-SOD levels, PINK1/PARKIN, PGC1α expression, LC3B, sirtuin-3 area percentage and evident increase in H2O2 level, P62, cytochrome-C area percentage with marked myocardial affection &more collagen deposition. AKI/EMPA demonstrated an obvious improvement in the previously mentioned results. Conclusion: EMPA ameliorated CRS3-induced myocardial damage through the inhibition of inflammation &mitochondrial oxidative-stress in addition to mitophagy &mitochondrial biogenesis activation. 

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