ALKBH5 induces macrophage activation to promote renal fibrosis via Retnla

Renal fibrosis is a common pathological endpoint of various chronic kidney diseases. Macrophages play an important role in the pathophysiological process of renal fibrosis. However, the exact function and molecular mechanism of macrophages during renal fibrosis remain unclear. In this study, we found an increased expression of RNA demethylase AlkB Homolog 5 (ALKBH5) in macrophages from the mice with unilateral ureteral obstruction (UUO) and TGF-β treatments bone marrow-derived macrophages. Macrophage-specific ALKBH5 knockout could significantly alleviate renal fibrosis in UUO mice and decrease the infiltration of macrophages in the kidneys. Further studies showed that ALKBH5 deficiency reduced M2a macrophage polarization and the expression of TGF-β1, Arg1, and CD206 both <i>in vivo</i> and <i>in vitro</i>. RNA sequencing indicated that Resistin-like alpha (Retnla) was the downstream target of ALKBH5, and treatment with recombinant Retnla abrogated the effect of ALKBH5 deficiency on renal fibrosis. We conclude that ALKBH5-dependent regulation of macrophage and kidney fibrosis progression through Retnla represents a novel strategy for patients with chronic kidney disease.

肾纤维化是多种慢性肾脏疾病共有的病理终末结局。巨噬细胞在肾纤维化的病理生理过程中发挥关键作用，但目前对于肾纤维化进程中巨噬细胞的确切功能与分子机制仍未阐明。本研究中，我们在单侧输尿管梗阻（UUO）模型小鼠及经转化生长因子β（TGF-β）处理的骨髓来源巨噬细胞中，均检测到RNA去甲基化酶AlkB同源物5（ALKBH5）的表达水平显著升高。巨噬细胞特异性敲除ALKBH5可显著缓解UUO模型小鼠的肾纤维化，并减少肾脏内巨噬细胞的浸润。进一步研究表明，ALKBH5缺失可在体内（in vivo）及体外（in vitro）抑制M2a型巨噬细胞极化，并降低转化生长因子β1（TGF-β1）、精氨酸酶1（Arg1）及CD206的表达水平。RNA测序结果显示，抵抗素样α（Retnla）是ALKBH5的下游靶基因；重组Retnla处理可逆转ALKBH5缺失对肾纤维化的改善作用。综上，ALKBH5通过调控Retnla进而影响巨噬细胞功能与肾纤维化进展的通路，为慢性肾脏疾病患者提供了全新的治疗策略。