Anti-Na+/K+-ATPase DR antibody attenuates UUO-induced renal fibrosis through inhibition of Na+/K+-ATPase?1-dependent HMGB1 release
Anti-Na+/K+-ATPase DR antibody attenuates UUO-induced renal fibrosis through inhibition of Na+/K+-ATPase?1-dependent HMGB1 release
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DOI：
10.1016/j.intimp.2023.109826
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发表时间：
2023-02-09
影响因子：
5.6
通讯作者：
Xue，Wu-jun
中科院分区：
文献类型：
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作者：
Zheng，Jin;Lan，Ping;Xue，Wu-jun
Na+/K+-ATP酶（NKA）活性降低和NKAα1表达减少参与肾脏疾病的病理过程。NKA介导的Src激活不是NKA相关肾纤维化的唯一原因。在本研究中，我们发现在UUO小鼠模型中，NKAα1的遗传减少表现出加重的肾小管间质病变和纤维化。用针对NKAα1亚基胞外DR区（DRm 217）的抗体激活NKAα1可预防UUO诱导的肾小管间质病变，保护肾功能并减少肾纤维化。进一步的研究表明，与NKAα1+/+（WT）小鼠相比，NKAα1缺陷小鼠在UUO手术时表现出较高的炎症因子表达。DRm 217可减轻UUO小鼠模型中炎症细胞浸润，抑制NF-κB磷酸化，降低炎症因子表达。释放的HMGB 1可触发炎症反应并促进肾纤维化。在UUO小鼠模型中，肾小管细胞或NKAα1+/-小鼠中NKA的敲除与对HMGB 1释放的更易感性相关。DRm 217通过抑制HMGB 1的释放发挥抗肝纤维化作用。此外，AMPK活化参与DRm 217抑制HMGB 1释放的作用。我们的研究结果表明，NKAα1是肾纤维化的调节因子，其DR区是其新的靶点。
Reduced Na+/K+-ATPase (NKA) activity and NKAα1 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 NKAα1 exhibited exacerbated tubulointerstitial lesions and fibrosis in the UUO mice model. Activation of NKAα1 with an antibody against the extracellular DR region of the NKAα1 subunit (DRm217) prevented UUO-induced tubulointerstitial lesions, preserved kidney function, and decrease renal fibrosis. Further studies revealed that NKAα1 deficiency mice exhibited high inflammation factors expression when they suffered UUO surgery, compared with NKAα1+/+(WT) mice. DRm217 alleviated inflammatory cell infiltration, suppress NF-κB 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 NKAα1+/-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 NKAα1 is a regulator of renal fibrosis and its DR-region is a novel target on it.