HO-1 Overexpressed Mesenchymal Stem Cells Ameliorate Sepsis-Associated Acute Kidney Injury by Activating JAK/stat3 Pathway.

ABSTRACT

BACKGROUND: Stem cell therapy has been increasingly used in the treatment of sepsis-associated acute kidney injury (AKI). Engineering stem cells, through genetic method, for optimized therapeutic outcome is a desirable strategy, which requires clear understanding of molecular mechanism underlying the interaction between stem cells and damaged kidney. The aim of this study is to evaluate the therapeutic effects of HO-1 overexpressed mesenchymal stem cells (MSCs) in AKI and investigate the role of JAK/stat3 pathway in the treatment strategy. METHOD: HO-1 was overexpressed in human MSCs with transfection of the expression plasmid. Quantitative RT-PCR was used to validate HO-1 overexpression. Sepsis was induced by the Cecal ligation and puncture (CLP) in mice. Survival of the treated mice were monitored and compared to that of the untreated mice. Biochemical analysis of serum biomarkers including colony forming unit (CFU), Creatinine (Cr) and blood urea nitrogen (BUN) was acquired and acute tubular necrosis (ATN) was measured. The extent of kidney injury was assessed through H&E staining of the kidney sections. Inflammatory factors were also compared between the two groups. Western blot was used to analyze the role of JAK/stat3 signaling pathway in this treatment strategy. RESULTS: MSCs with HO-1 overexpression markedly improved the survival of the AKI mice, accompanied by decreasing of CFU, Cr BUN in serum and ATN scores. H&E staining validated that kidney tissue demonstrated morphology that was similar to normal kidney in HO-1 MSC treated group. Inflammatory factors were also reduced by HO-1 MSC treatment. Western blot analysis indicated an upregulation of key proteins in the JAK/stat3 pathway. CONCLUSIONS: HO-1 overexpression enhances therapeutic effect of MSCs in AKI, which is presumably attributed to the activation of JAK/stat3 signaling pathway.