Erythropoietin alleviate obstructive renal fibrosis by regulating immunity and inflammation through miR-21-5p/SPRY1/ERK1/2/NF-κB pathway inhibition

The important role of erythropoietin (EPO) in the treatment of renal fibrosis induced by urinary tract obstruction has been documented in numerous studies; however, its underlying molecular mechanisms are not yet fully understood, particularly its role in regulating immunity and inflammation. Previous studies have revealed that miR-21 can influence the progression of organ fibrosis by regulating inflammation via activation of the SPRY1/ERK/NF-κB pathway. Additionally, several studies have shown that EPO can exert therapeutic effect by regulating microRNA expression. However, the effect of EPO on miR-21, the NF-κB system (which is associated with innate immunity and inflammation), and specific signaling pathways in the context of obstructive renal fibrosis has rarely been reported. In the present study, we employed a mouse model of unilateral ureteral obstruction (UUO) in which the left ureters were ligated and treated the mice with low-dose rhEPO (100 U/kg) for 7 days, and validated the possible signaling pathway through vitro experiments using HK-2 cells. We found that low-dose rhEPO treatment alleviated the fibrosis and inflammation of obstructive kidneys in mice and the upregulation of miR-21-5p and activation of SPRY1/ERK/NF-κB pathway could be reversed by rhEPO treatment in vivo and vitro studies. To the best of our knowledge, this is the first demonstration that EPO exerts anti-fibrotic effect in obstructive renal fibrosis by regulating immunity and inflammation through miR-21-5p/SPRY1/ERK/NF-kB axis.