Molecular and Cellular Mechanisms Involved in Adipose-derived stem cell and their extracellular vesicles in an Experimental Model of Cardio- renal Syndrome type 3: Histological and Biochemical Study

Abstract

A cardio-renal syndrome (CRS) is a medical condition in which kidney problems are accompanied by heart problems and diagnosed when acute kidney injury contributes to the development of acute cardiac injury. Regenerative medicine is becoming increasingly interested in adipose stem cells. We evaluated the effect of both adipose-derived stem cell extracellular vesicles (ADSCs-EVs) and adipose stem cells (ADSCs) on an experimental model of CRSIII. In this study, isolation, and further identification of ADSCs and ADSCs-EVs by transmission electron microscopy and flow cytometric analysis. Cardio-renal syndrome in rats was induced by renal artery ligation RAL followed by a single dose injection of both ADSCs and ADSCs-EVs in separate groups. The effects of ADSCs-EVs and ADSCs against induced CRSIII were evaluated by both renal and cardiac oxidant/antioxidant biomarkers, renal function, and mRNA gene expression quantitation for atrial natriuretic peptide (ANP), p300, and myocyte enhancer factor 2 (MEF2C and MEF2A), as well as myocardin (MYOCD), as molecules associated with cardiac hypertrophy. Additionally, histological and immunohistochemical studies of cardiac and renal tissues were done. ADSCs-EVs were effectively isolated and characterized. ADSCs-EVs and ADSCs reversed induced CRSIII, evidenced by considerably decreased serum urea and creatinine levels. Returned oxidant/antioxidant stability, and decreased caspase 3-mediated apoptotic programmed cell death in cardiac and renal tissues. Additionally, they led to successful down-regulation of hypertrophic cardiac genes levels and reversed histopathological cardiac and renal injures. ADSCs-derived extracellular vesicles and ADSCs injection restored damaged cardiac and renal tissue and improved its function greatly following induced CRSIII. They could therefore be useful as a means of protecting the heart from the deleterious effects of acute renal injury and reprogramed injured cardiac cells by activating regenerative processes. Simple summaryCardiorenal syndrome (CRS) type III is a subcategory of CRS whereby acute kidney injury (AKI) could contribute to the development of acute cardiac dysfunction. This study provided innovatory data regarding the role of adipose-derived stem cell extracellular vesicles ADSCs-EVs and adipose stem cells (ADSCs) in acute renal and cardiac dysfunction and renal biopsy specimens in the form of interstitial inflammation/tubular degeneration. The main cause of renal and cardiac dysfunction is identified to be the activation and accumulation of inflammatory cells and oxidants in the interstitium, surrounded by increased amounts of extracellular matrix, and ADSCs-EVs have been proposed as a contributor factor. The study has evidenced that both ADSCs-EVs and adipose stem cells display beneficial effects on renal and cardiac tissues survival in terms of the frequent occurrence of cardio-renal syndrome, ADSC-EVs treatment repaired damaged renal and cardiac tissues and recovered their function. ADSC-EVs reversed the effects of cardio-renal syndrome and reprogramed injured cells by activating regenerative processes. The clinical significance of the results presented in future studies needs to be investigated further.