Exosomes released by human umbilical cord mesenchymal stem cells protect against renal interstitial fibrosis through ROS-mediated P38MAPK/ERK signaling pathway.

Mesenchymal stem cells (MSCs) and their conditioned medium attenuate renal fibrosis in an irreversible model of unilateral ureteral obstruction (UUO). However, the key components that play a role in the paracrine effects of MSCs and their mechanisms of action are not well understood. Therefore, in this study, we investigated whether exosomes released by human umbilical cord mesenchymal stem cells (hucMSC-Ex) would be able to attenuate renal fibrosis in an irreversible model of UUO and further explored potential mechanisms. In vivo, rats were divided into four groups: sham operation, sham operation transplanted with hucMSC-Ex, UUO, and UUO transplanted with hucMSC-Ex. hucMSC-Ex was administered via the left renal artery after total ligation of the left ureter. Rats were sacrificed after 14 days of obstruction. Renal function such as serum creatinine (Scr) or blood urea nitrogen (BUN) were monitored over the period. Histological changes, proliferation and apoptosis in tubular epithelial cells, and the levels of oxidative stress were measured. In vitro, NRK-52E cells were incubated with or without 5 ng/ml TGF-β1 and co-incubated with or without hucMSC-Ex for 48 h. Apoptosis and the levels of oxidative stress of NRK-52E cells were also measured. In the UUO group, the level of BUN and Scr, and the level of apoptosis and oxidative stress were all increased. In addition, the renal tubular injury and tubulointerstitial fibrosis were evident. However, all the above indices decreased significantly after treatment with hucMSC-Ex. In vitro, hucMSC-Ex significantly inhibited TGF-β1-induced apoptosis of NRK-52E cells by altering the production of ROS. Furthermore, it was observed that hucMSC-Ex inhibited apoptosis by inhibiting the activation of p38 mitogen-activated protein kinase (p38MAPK)/extracellular-signal-regulated kinase (ERK) 1/2 pathway. In conclusion, the results showed that hucMSC-Ex had positive effects towards UUO-induced renal fibrosis and apoptosis of renal tubular epithelial cells, and its mechanism of action was associated with inhibition of ROS-mediated p38MAPK/ERK signaling pathway. These data suggest the potential application of hucMSC-Ex in the treatment of chronic kidney disease, and also reveal the underlying mechanism of hucMSC-Ex action. AJTR