Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
Int J Biol Sci. 2022 Sep 1;18(15):5624-5640. doi: 10.7150/ijbs.75994. eCollection 2022.
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and is one of the leading causes of end-stage kidney disease. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that play important roles in various diseases, yet their roles in DKD are poorly understood. CircRNA HIPK3 (circHIPK3), a highly conserved circRNA, is closely related to various cellular functions, including cell proliferation and apoptosis. The association between circHIPK3 and diabetic complications has been well demonstrated in multiple previous studies. However, the role of circHIPK3 in podocyte injury in DKD remains unclear. Herein, we discovered that circHIPK3 expression is markedly elevated in cultured podocytes under high-glucose (HG) conditions and glomeruli of diabetic mice, which is closely associated with podocyte injury in DKD. Functionally, lentivirus-mediated knockdown of circHIPK3 dramatically suppresses HG-induced podocyte apoptosis . Therapeutically, silencing circHIPK3 by adeno-associated virus-mediated RNA interference ameliorates podocyte injury and albuminuria in STZ-induced diabetic mice. Mechanistically, circHIPK3 facilitates the enrichment of fused in sarcoma (FUS) on the ectodysplasin A2 receptor (EDA2R) promoter, resulting in the upregulation of EDA2R expression and activation of apoptotic signaling. Taken together, these results indicate circHIPK3/FUS/EDA2R axis as a therapeutic target for podocyte injury and DKD progression.
糖尿病肾病（DKD）是糖尿病的一种主要微血管并发症，也是终末期肾病的主要病因之一。环状 RNA（circRNA）是一类内源性非编码 RNA，在各种疾病中发挥重要作用，但它们在 DKD 中的作用知之甚少。circRNA HIPK3（circHIPK3）是一种高度保守的 circRNA，与多种细胞功能密切相关，包括细胞增殖和凋亡。circHIPK3 与糖尿病并发症的关联在之前的多项研究中已经得到了很好的证明。然而，circHIPK3 在 DKD 中足细胞损伤中的作用尚不清楚。在此，我们发现高糖（HG）条件下培养的足细胞和糖尿病小鼠肾小球中 circHIPK3 的表达明显升高，与 DKD 中的足细胞损伤密切相关。功能上，慢病毒介导的 circHIPK3 敲低显著抑制 HG 诱导的足细胞凋亡。在治疗上，腺相关病毒介导的 RNA 干扰沉默 circHIPK3 可改善 STZ 诱导的糖尿病小鼠的足细胞损伤和蛋白尿。机制上，circHIPK3 促进肉瘤融合（FUS）在外胚层发育不良蛋白 A2 受体（EDA2R）启动子上的富集，导致 EDA2R 表达上调和凋亡信号激活。综上所述，这些结果表明 circHIPK3/FUS/EDA2R 轴是治疗足细胞损伤和 DKD 进展的靶点。
