Aims: This study aimed to detect the effect of angiotensin-converting enzyme (ACE) 2-modified mesenchymal stem cells (MSCs) on glomerular fibrosis in vitro and in vivo and investigate the underlying molecular mechanism.
Methods: MSCs transduced with the ACE2 gene (MSCs-ACE2) were cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation. MSCs-ACE2 were transplanted into streptozotocin-induced diabetic rats. Physical, biochemical and morphological parameters were measured, and fibrotic indicators and renin-angiotensin system (RAS) components in GMCs and kidney tissues were assessed.
Results: The transduction efficiency of MSCs was as high as 85%. The modified MSCs secreted soluble ACE2 protein into the culture medium. After transplantation into rats with diabetes, MSCs-ACE2 targeted injured kidneys and enhanced local expression of ACE2. Compared with MSC treatment alone, MSC-ACE2 treatment was superior in reducing albuminuria and improving glomerulosclerosis. In vitro and in vivo, MSCs-ACE2 were more beneficial than MSCs alone in decreasing Ang II and increasing Ang1-7, thereby inhibiting the detrimental effects of Ang II accumulation by downregulating collagen I and fibronectin (FN) expression and inhibiting the transforming growth factor (TGF-β)/Smad pathway.
Conclusions: MSCs modified with ACE2 therapy have additional benefits to the progression of diabetic nephropathy (DN) by inhibiting renal RAS activation and reducing glomerular fibrosis.
Keywords: Angiotensin II; Angiotensin-converting enzyme 2; Diabetic nephropathy; Glomerular fibrosis; Mesenchymal stem cells.
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