Sfrp2 promotes renal dysfunction of diabetic kidney disease via modulating Fzd5-induced cytosolic calcium ion concentration and CaMKII/Mek/Erk pathway in mesangial cells

作者全名："Lv, Dan; Lin, Ziyue; Liao, Xiaohui; Peng, Rui; Liu, Handeng; Wu, Tianhui; Wu, Keqian; Sun, Yan; Zhang, Zheng"

作者地址："[Lv, Dan; Lin, Ziyue; Wu, Tianhui; Wu, Keqian; Sun, Yan; Zhang, Zheng] Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Chongqing 400016, Peoples R China; [Liao, Xiaohui] Chongqing Med Univ, Dept Nephrol, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Peng, Rui] Chongqing Med Univ, Dept Bioinformat, Chongqing 400016, Peoples R China; [Liu, Handeng] Chongqing Med Univ, Expt Teaching Ctr, Lab Tissue & Cell Biol, Chongqing 400016, Peoples R China"

通信作者："Sun, Y; Zhang, Z (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Chongqing 400016, Peoples R China."

来源：BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001113515900001

JCR分区：Q1

影响因子：6.2

年份：2024

卷号：1870

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：Sfrp2; Single -nucleus sequencing; Diabetic kidney disease; Mesangial cells; Cell proliferation

摘要："Objective: Mesangial 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 DKD in vitro and in vivo and explored the specific mechanisms. Results: By 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 verified in vitro and in 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 injury in vitro and in 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. Conclusion: Our study revealed a novel involvement for Sfrp2 in the regulation of MC function and the effect of Sfrp2 on cell proliferation and fibrosis of MC via the Fzd5/Ca2+/CaMKII/Mek/Erk pathway, implying that Sfrp2 may be a possible biomarker and therapeutic target for DKD."

基金机构："National Natural Science Foundation of China [82270876, 81970702]; Natural Sci-ence Foundation of Chongqing [CSTB2022NSCQ-MSX0126]; Top-notch Talents Program for graduate students of Chongqing Medical University, China [BJRC202208]"

基金资助正文："Grants This work was supported by National Natural Science Foundation of China Grant 82270876 and 81970702 (to Zheng Zhang) , Natural Sci-ence Foundation of Chongqing Grant CSTB2022NSCQ-MSX0126 (to Zheng Zhang) and the Top-notch Talents Program for graduate students of Chongqing Medical University, China BJRC202208 (to Dan Lv) ."