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

Erpeng Liu¹Xiao Sun²Qilong Liu¹Dongyi Jin¹Guihong Li¹Huayan Zhao¹Hao Sun³Yuming Du^1*

• ¹First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
• ²Henan academy of Innovations in Medical Science, Zhengzhou, China
• ³Anyang Center for Disease Control and Prevention, Anyang, China

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 (100U/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-κB axis.