P0026METFORMIIN IMPROVES DYSFUNCTION OF MESENCHYMAL STEM CELLS ASSOCIATED WITH CHRONIC KIDNEY DISEASE VIA SENESCENCE INHIBITION

Abstract

Abstract Background and Aims Mesenchymal stem cells (MSC) are promising source of cell-based regenerative therapy; however, adequate cell functionality is a critical factor for the success of autotransplantation. Method We investigated the effects of metformin on chronic kidney disease (CKD)-associated cellular senescence using MSC isolated from sham operated and subtotal nephrectomized mice and further explored the protective role of metformin-treated CKD MSC in renal progression. Results When compared to normal MSC, MSC isolated from CKD mice displayed reduced proliferation and early senescence as determined by enlarged cell morphology, increased oxidative stress, accumulation of DNA damage response marker p53 binding protein 1 (53BP1), phospho p53, p16INK4a, and β-gal expression, and decreased cyclin-dependent kinase 4 (CDK4) and cyclin D. CKD MSC exhibited activation of NFκB resulting in expression of senescence-associated secretory phenotype (SASP) factors compared to normal MSC. All of these changes were significantly prevented by metformin treatment. In vivo, metformin-treated CKD MSC attenuated inflammation and fibrosis in UUO kidney as compared to CKD MSC. Co-culture of LPS or TGF-β1-treated HK2 cells with metformin-treated CKD MSC markedly decreased LPS or TGF-β-induced tubular expression of proinflammatory markers and fibrogenesis when compared to CKD MSC suggesting paracrine action of CKD MSC enhanced by metformin treatment. Conclusion Our data suggest that metformin inhibits cellular senescence of CKD MSC and improves their renoprotective effects.