Anti-Na+/K+-ATPase DR antibody attenuates UUO-induced renal fibrosis through inhibition of Na+/K+-ATPase?1-dependent HMGB1 release

Reduced Na+/K+-ATPase (NKA) activity and NKA alpha 1 expression are engaged in the pathologies of renal diseases. NKA-mediated Src activation is not the only reason for NKA-related renal fibrosis. In this study, we found that genetic reduction of NKA alpha 1 exhibited exacerbated tubulointerstitial lesions and fibrosis in the UUO mice model. Activation of NKA alpha 1 with an antibody against the extracellular DR region of the NKA alpha 1 subunit (DRm217) prevented UUO-induced tubulointerstitial lesions, preserved kidney function, and decrease renal fibrosis. Further studies revealed that NKA alpha 1 deficiency mice exhibited high inflammation factors expression when they suffered UUO surgery, compared with NKA alpha 1+/+ (WT) mice. DRm217 alleviated inflammatory cell infiltration, suppress NF-kappa B phosphorylation, and decreased inflammatory factors expression in the UUO mice model. Released HMGB1 can trigger the inflammatory response and contribute to renal fibrosis. Knockdown of NKA in renal tubular cells or in NKA alpha 1+/- mice was associated with more susceptibility to HMGB1 release in the UUO mice model. DRm217 exerted its antifibrotic effect via inhibiting HMGB1 release. Furthermore, AMPK activation participates in the effect of DRm217 on inhibiting HMGB1 release. Our findings suggest that NKA alpha 1 is a regulator of renal fibrosis and its DR-region is a novel target on it.

Automated summary

Reduced Na+/K+-ATPase (NKA) activity and NKA alpha 1 expression are implicated in the pathogenesis of renal diseases. NKA alpha 1 deficiency exacerbates tubulointerstitial lesions and fibrosis in a mouse model of UUO. Activation of NKA alpha 1 by an antibody against its extracellular DR region (DRm217) prevents UUO-induced tubulointerstitial lesions, preserves kidney function, and reduces renal fibrosis.