Mesenchymal Stem Cells Modified with Angiotensin Converting Enzyme 2 are Superior in Ameliorating Inflammation and Oxidative Stress in Diabetic Nephropathy

Abstract: Background The purpose of this study is to detect the effect of angiotensin converting enzyme 2 (ACE2)-modified mesenchymal stem cells (MSCs) on inflammation and oxidative stress in diabetic nephropathy (DN) and investigate the underlying mechanism. Methods MSCs transduced with a lentiviral vector overexpressing ACE2 (MSCs-ACE2) were transplanted in streptozotocin (STZ)-induced diabetic rats and cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation in vitro. Biochemical parameters were measured. Extracellular matrix (ECM) proteins, inflammation, oxidative stress indicators and renin-angiotensin system (RAS) elements were detected. To explore possible molecular mechanisms, the phosphorylation levels of p38 MAPK, and IκB-α in GMCs were measured by Western blotting. Results MSCs-ACE2 treatment significantly decreased urinary albumin excretion and ECM deposition in the mesangium, downregulated the expression of inflammatory cytokines, decreased the production of ROS and MDA, increased the activity of SOD and the ratio of GSH to GSSG than MSCs treatment alone in vivo. In vitro, after MSC-ACE2 treatment, ACE2 expression in GMCs was significantly upregulated, and its product Ang1-7 correspondingly increased, the indicators of inflammation and oxidative stress were ameliorated by downregulation of Ang II expression in GMCs; moreover, the phosphorylation levels of p38 MAPK and IκB-α protein were significantly downregulated. Conclusions Based on these results, we believed that MSCs modified with ACE2 therapy exhibited additional benefits on the progression of DN by inhibiting renal RAS activation and reducing inflammation and oxidative stress in vivo and in vitro. The possible mechanisms were potentially inhibition of p38 MAPK and NF-kB pathway activation.