Sfrp2 promotes renal dysfunction of diabetic kidney disease via modulating Fzd5-induced cytosolic calcium ion concentration and CaMKII/Mek/Erk pathway in mesangial cells
Sfrp2 promotes renal dysfunction of diabetic kidney disease via modulating Fzd5-induced cytosolic calcium ion concentration and CaMKII/Mek/Erk pathway in mesangial cells
复制标题
DOI：
10.1016/j.bbadis.2023.166933
复制
发表时间：
2023-11-15
影响因子：
6.2
通讯作者：
Zhang，Zheng
中科院分区：
文献类型：
--
作者：
Lv，Dan;Lin，Ziyue;Zhang，Zheng
肾小球系膜细胞（Mesangial cells，MCs）是维持肾小球完整性的重要细胞，其异常增殖导致包括糖尿病肾病（Diabetic kidney disease，DKD）在内的多种肾小球疾病。虽然高血糖可导致MCs损伤，但其分子机制尚不清楚。本研究旨在探讨分泌型卷曲相关蛋白2（Sfrp 2）对DKD大鼠MC增殖的影响及其机制。结果通过对瘦素受体缺陷db/db小鼠和对照db/m小鼠的肾细胞进行snRNA-seq分析，发现Sfrp 2在DKD大鼠MC中的表达高于其他固有肾细胞，并进一步在体外和体内进行了验证。我们还发现Sfrp 2在DKD患者中的表达显著上调，并且与肾功能相关，表明Sfrp 2可能作为DKD患者的独立生物标志物。在功能上，我们发现Sfrp 2的丢失和获得影响细胞内Ca ~（2+）浓度、MC的细胞增殖和纤维化、蛋白尿和肾损伤。机制上，我们确定c-Jun作为Sfrp 2的转录因子促进其转录，和Ca 2+信号相关蛋白卷曲受体5（Fzd 5）作为Sfrp 2的结合蛋白。结论Sfrp 2可能参与了DKD大鼠MC功能的调节，并可能通过Fzd 5/Ca 2 +/CaMKII/Mek/Erk途径影响MC增殖和纤维化。提示Sfrp 2可能是DKD的生物标志物和治疗靶点。
ObjectiveMesangial cells (MCs) in the kidney play central role in maintaining glomerular integrity, and their abnormal proliferation leads to major glomerular diseases including diabetic kidney disease (DKD). Although high blood glucose elicits MCs impairment, the underlying molecular mechanism is poorly understood. The present study aimed to investigate the effect of secreted frizzled-related protein 2 (Sfrp2) from single-nucleus RNA profiling on MC proliferation of DKDin vitroandin vivoand explored the specific mechanisms.ResultsBy snRNA-seq analysis of isolated renal cells from leptin receptor-deficient db/db mice and control db/m mice, we found that Sfrp2 was increased in the MCs of DKD in comparison to other intrinsic renal cells, which was further verifiedin vitroandin vivo. We also found that the expression of Sfrp2 was significantly upregulated in DKD patients and correlated with renal function, demonstrating that Sfrp2 might serve as an independent biomarker for DKD patients. Functionally, we showed the loss and acquisition of Sfrp2 affected cytosolic Ca2+concentration, cell proliferation and fibrosis of MC, albuminuria and kidney injuryin vitroandin vivo. Mechanistically, we identify c-Jun as a transcription factor of Sfrp2 promoting its transcription, and the Ca2+signaling related protein frizzled receptor 5 (Fzd5) as the binding protein of Sfrp2. And we further found Sfrp2 promoted Fzd5-induced cytosolic Ca2+concentration and the downstream CaMKII/Mek/Erk pathway activation, leading to MC proliferation and fibrosis in DKD.ConclusionOur study revealed a novel involvement for Sfrp2 in the regulation of MC function and the effect of Sfrp2 on cell proliferation and fibrosis of MCviathe Fzd5/Ca2+/CaMKII/Mek/Erk pathway, implying that Sfrp2 may be a possible biomarker and therapeutic target for DKD.