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Intrarenal Hypoxic Mesenchymal Stem Cells Transplantation Enforces Homing and Paracrine Effects to Ameliorate Anti‐Thy1.1‐Induced Nephritis in Rats

In acute glomerlonephritis, activated resident cells or infiltrated inflammatory cells‐derived oxidative stress evoked GRP78‐mediated endoplasmic reticulum stress, Bax/Bcl‐2 family‐related apoptosis and Beclin‐1/LC3‐II‐mediated autophagy leading to glomerular injury. Mesenchymal stem cells (MSC) provide excellent self‐renewal and proliferation ability. In addition, MSC may release high levels of growth factors, cytokines and prostaglandins in the microenvironment by the paracrine mechanism to enhance cell proliferation, survival and angiogenesis to repair injuried tissue. Under hypoxic condition, MSC (HMSC) can not only prevent senescence but also increase differentiation efficiency. We aimed to evaluate the therapeutic effects and mechanisms of MSC or HMSC on anti‐thy1.1‐induced glomerulonephritis in the rats. Our results found that intrarenal arterial administration of MSC or HMSC (1×105, 2×105, 5×105 cells) can successfully implant in the glomeruli and proximal and distal tubules. Anti‐thy1.1 induced glomerulonephritis by the appearance of mesangial cell lysis, increase of collagen by Masson stain, collagen IV expression, ED‐1 infiltration, GRP78/endoplasmic reticulum (ER) stress, Bax/Bcl‐2/Caspase 3/PARP‐mediated apoptosis, Beclin‐1/LC3 II‐mediated autophagy and elevated urinary protein levels in nephritic rats. HMSC was more efficient than MSC significantly and dose‐dependently in reducing PAS‐injuried score, ED‐1 infiltration, GRP78/ER‐stress Bax/Bcl‐2/Caspase 3/PARP‐mediated apoptosis, Beclin‐1/LC3 II‐mediated autophagy, Masson stain, collagen IV expression and elevated urinary protein levels in nephritic rats. HMSC was more efficient than MSC in the reappearance of OX‐7 stain (Thy1.1 stain) in the nephritic glomeruli. Our results indicate that HMSC through higher efficiency in homing and paracrine effects attenuate autophagy, apoptosis, ER stress, inflammation and glomerular sclerosis in acute nephritis.