Overexpression of miR‐19a and miR‐20a in iPS‐MSCs preserves renal function of chronic kidney disease with acute ischaemia‐reperfusion injury in rat

This study tested the hypothesis that therapy with double overexpression of miR‐19a‐3p and miR‐20a‐5p (miR(DOE)) to human inducible pluripotent stem cell–derived mesenchymal stem cells (iPS‐MSCs) was superior to iPS‐MSCs alone for preserving renal function in rat with pre‐existing chronic kidney disease (CKD), followed by ischaemia‐reperfusion (IR) injury. In vitro study demonstrated that the protein expressions of oxidative stress (NOX‐1/NOX‐2/NOX4/oxidized protein/p22phox), inflammatory downstream signalling (TLR2&4/MyD88/TRAF6/IKK‐ß/p‐NFκB/IL‐1ß/IL‐6/MMP‐9) and cell apoptosis/death signalling (cleaved caspase‐3/mitochondrial Bax/p‐ERKs/p‐JNK/p‐p38) at time‐points of 24‐hour/48‐hour cell cultures were significantly increased in p‐Cresol‐treated NRK‐52E cells than in the control that was significantly reversed by miR‐19a‐3p‐transfected iPS‐MSC (all P < .001). Animals were categorized into group 1 (sham‐operated control), group 2 (CKD‐IR), group 3 (CKD‐IR + oligo‐miR(DOE) of iPS‐MSCs/6.0 ×10(5)/intra‐renal artery transfusion/3 hours after IR procedure), group 4 (CKD‐IR + iPS‐MSCs) and group 5 (CKD‐IR + miR(DOE) of iPS‐MSCs/6.0 ×10(5/)intra‐renal artery transfusion/3 hour after IR procedure). By day 35, the creatinine/BUN levels were lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3 and 4 (all P < .0001) but they showed no difference between the latter two groups. The protein expressions of oxidative stress, inflammatory downstream signalling and cell apoptosis/death signalling exhibited an identical pattern of creatinine level among the five groups (all P < .00001). Also, the microscopic findings demonstrated that the kidney injury score/fibrotic area/number of inflammatory cells (CD14+/CD68+) exhibited an identical pattern of creatine level (all P < .0001). The miR(DOE) of iPS‐MSCs was superior to iPS‐MSCs for preserving the residual kidney function and architecture in CKD‐IR rat.