Xie Ting, Xia Zunen, Wang Wei, Zhou Xiangjun, Xu Changgeng
Department of Woman's Health Care, Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
Front Cell Dev Biol. 2021 Feb 11;9:608396. doi: 10.3389/fcell.2021.608396. eCollection 2021.
Tubulointerstitial fibrosis is both a pathological manifestation of chronic kidney disease and a driving force for the progression of kidney disease. A previous study has shown that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) is involved in lung fibrogenesis. However, the role of BMPER in renal fibrosis remains unknown. In the present study, the expression of BMPER was examined by real-time PCR, Western blot and immunohistochemical staining. The effects of BMPER on tubular dedifferentiation and fibroblast activation were analyzed in cultured HK-2 and NRK-49F cells. The effects of BMPER were dissected in unilateral ureteral obstruction (UUO) mice by delivery of BMPER gene via systemic administration of plasmid vector. We reported that the expression of BMPER decreased in the kidneys of UUO mice and HK-2 cells. TGF-β1 increased inhibitor of differentiation-1 (Id-1) and induced epithelial mesenchymal transition in HK-2 cells, and knockdown of BMPER aggravated Id-1 up-regulation, E-cadherin loss, and tubular dedifferentiation. On the contrary, exogenous BMPER inhibited Id-1 up-regulation, prevented E-cadherin loss and tubular dedifferentiation after TGF-β1 exposure. In addition, exogenous BMPER suppressed fibroblast activation by hindering Erk1/2 phosphorylation. Knockdown of low-density lipoprotein receptor-related protein 1 abolished the inhibitory effect of BMPER on Erk1/2 phosphorylation and fibroblast activation. Moreover, delivery of BMPER gene improved renal tubular damage and interstitial fibrosis in UUO mice. Therefore, BMPER inhibits TGF-β1-induced tubular dedifferentiation and fibroblast activation and may hold therapeutic potential for tubulointerstitial fibrosis.
肾小管间质纤维化既是慢性肾脏病的一种病理表现，也是肾脏病进展的驱动因素。先前的一项研究表明，骨形态发生蛋白结合内皮细胞前体衍生调节剂（BMPER）参与肺纤维化的发生。然而，BMPER在肾纤维化中的作用仍不清楚。在本研究中，通过实时PCR、蛋白质免疫印迹和免疫组织化学染色检测了BMPER的表达。在培养的HK-2和NRK-49F细胞中分析了BMPER对肾小管去分化和成纤维细胞活化的影响。通过经质粒载体全身给药递送BMPER基因，在单侧输尿管梗阻（UUO）小鼠中剖析了BMPER的作用。我们报道，UUO小鼠肾脏和HK-2细胞中BMPER的表达降低。TGF-β1增加分化抑制因子-1（Id-1）并诱导HK-2细胞发生上皮-间质转化，而敲低BMPER会加重Id-1上调、E-钙黏蛋白丢失和肾小管去分化。相反，外源性BMPER抑制Id-1上调，防止TGF-β1刺激后E-钙黏蛋白丢失和肾小管去分化。此外，外源性BMPER通过阻碍Erk1/2磷酸化抑制成纤维细胞活化。敲低低密度脂蛋白受体相关蛋白1消除了BMPER对Erk1/2磷酸化和成纤维细胞活化的抑制作用。此外，递送BMPER基因改善了UUO小鼠的肾小管损伤和间质纤维化。因此，BMPER抑制TGF-β1诱导的肾小管去分化和成纤维细胞活化，并可能对肾小管间质纤维化具有治疗潜力。
