Induced Pluripotent Stem Cells without c-Myc Attenuate Acute Kidney Injury via Downregulating the Signaling of Oxidative Stress and Inflammation in Ischemia–Reperfusion Rats

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Abstract
Induced pluripotent stem (iPS) cells have potential for multilineage differentiation and provide a resource for stem cell-based treatment. However, the therapeutic effect of iPS cells on acute kidney injury (AKI) remains uncertain. Given that the oncogene c-Myc may contribute to tumorigenesis by causing genomic instability, herein we evaluated the therapeutic effect of iPS cells without exogenously introduced c-Myc on ischemia–reperfusion (I/R)-induced AKI. As compared with phosphate-buffered saline (PBS)-treated group, administration of iPS cells via intrarenal arterial route into kidneys improved the renal function and attenuated tubular injury score at 48 h after ischemia particularly at the dose of 5 × 105 iPS cells. However, a larger number of iPS cells (5 × 107 per rat) diminished the therapeutic effects for AKI and profoundly reduced renal perfusion detected by laser Doppler imaging in the reperfusion phase. In addition, the green fluorescence protein-positive iPS cells mobilized to the peritubular area at 48 h following ischemia, accompanied by a significant reduction in infiltration of macrophages and apoptosis of tubular cells, and a remarkable enhancement in endogenous tubular cell proliferation. Importantly, transplantation of iPS cells reduced the expression of oxidative substances, proinflammatory cytokines, and apoptotic factors in I/R kidney tissues and eventually improved survival in rats of ischemic AKI. Six months after transplantation in I/R rats, engrafted iPS cells did not result in tumor formation in kidney and other organs. In summary, considering the antioxidant, anti-inflammatory, and antiapoptotic properties of iPS cells without c-Myc, transplantation of such cells may be a treatment option for ischemic AKI.

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