Abstract
Current therapeutic options for acute kidney injury (AKI) are limited to the use of supportive measures and dialysis. A recent approach that has sparked great interest and gained enormous popularity is the implantation of stem cells to repair acutely damaged kidney organ. Hypoxia inducible factor-1α (HIF-1α) is effective in protecting the kidney from ischemia and nephrotoxicity. In this study, we investigated whether HIF-1α-modified adipose-derived stem cells (ASCs) had an enhanced protective effect on cisplatin-induced kidney injury in vivo. Cisplatin-induced AKI was established in nude mice. Our study demonstrated that HIF-1α-modified ASCs obviously promoted the recovery of renal function, ameliorated the extent of histologic injury and reduced renal apoptosis and inflammation, but HIF-1α-modified ASCs homed to kidney tissues at very low levels after transplantation. In addition, we also found that HIF-1α-modified ASCs significantly increased HO-1 expression in cisplatin-induced AKI in vivo. Thus, our study indicated HIF-1α-modified ASCs implantation could provide advanced benefits in the protection again AKI, which will contribute to developing a new therapeutic strategy for the treatment of AKI.
Highlights
Recent advances have improved our understanding of acute kidney injury (AKI), AKI remains a high risk factor for mortality and morbidity
The number of TUNEL-positive cells in the tubular epithelium was significantly increased in cisplatin-treated nude rats, and the apoptotic indexes were significantly reduced in nude rats that had received an infusion of EV-Human adipose-derived stem cells (hASC) and Hypoxia inducible factor-1α (HIF-1α) -hASCs (P < 0 .05 vs. model group), and the score of the apoptotic indexes was lowest in the Hypoxia-inducible factor (HIF)-1α -hASCs group (P < 0.05 vs. EV-hASCs; Fig. 2B)
We successfully delivered the HIF-1α gene into hASCs via a lentiviral vector, which increased the levels of HIF-1α expression and maintained their stem cell characteristics in vitro[19]
Summary
Protection of HIF-1α-hASCs on renal function and histology of cisplatin-induced AKI. EV-hASCs and HIF-1α -hASCs exhibited an obviously renoprotective effect, as reflected by lower BUN and SCr levels compared with the model group (P < 0 .05) (Fig. 1 A, B). Effect of HIF-1α-hASCs in reducing renal cell apoptosis of cisplatin-induced AKI. The number of TUNEL-positive cells in the tubular epithelium was significantly increased in cisplatin-treated nude rats, and the apoptotic indexes were significantly reduced in nude rats that had received an infusion of EV-hASCs and HIF-1α -hASCs (P < 0 .05 vs model group), and the score of the apoptotic indexes was lowest in the HIF-1α -hASCs group (P < 0.05 vs EV-hASCs; Fig. 2B). To investigate the effect of HIF-1α -hASCs on regulating inflammatory cytokines level, the immunohistology of RANTES, TNF-α and IL-10 was performed in renal tissue of mice suffering from cisplatin-induced AKI. The immunohistological area percentage of positive staining indicated that the expression of pro-inflammatory cytokines (RANTES and TNF-α ) was significantly increased in cisplatin-treated nude rats (P < 0 .05 vs other groups), and HIF-1α -hASCs obviously decreased the expression of pro-inflammatory cytokines (P < 0 .05 vs EV-hASCs). The immunohistological analysis of HO-1 protein was shown to be identical to its mRNA expression (Fig. 5)
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