Klotho inhibits renal ox-LDL deposition via IGF-1R/RAC1/OLR1 signaling to ameliorate podocyte injury in diabetic kidney disease

作者全名："Jiang, Wei; Gan, Chun; Zhou, Xindi; Yang, Qing; Chen, Dan; Xiao, Han; Dai, Lujun; Chen, Yaxi; Wang, Mo; Yang, Haiping; Li, Qiu"

作者地址："[Jiang, Wei; Gan, Chun; Zhou, Xindi; Yang, Qing; Chen, Dan; Xiao, Han; Wang, Mo; Yang, Haiping; Li, Qiu] Chongqing Med Univ, Pediat Res Inst, Natl Clin Res Ctr Child Hlth & Disorders, Dept Nephrol,Childrens Hosp,Chongqing Key Lab Pedi, Chongqing, Peoples R China; [Dai, Lujun] Guizhou Med Univ, Affiliated Hosp, Dept Pathol, Guiyang, Guizhou, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Dept Infect Dis,Minist Educ,Inst Viral Hepatitis, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis,Minist Educ, Chongqing, Peoples R China"

通信作者："Yang, HP; Li, Q (通讯作者)，Chongqing Med Univ, Pediat Res Inst, Natl Clin Res Ctr Child Hlth & Disorders, Dept Nephrol,Childrens Hosp,Chongqing Key Lab Pedi, Chongqing, Peoples R China."

来源：CARDIOVASCULAR DIABETOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001091438200004

JCR分区：Q1

影响因子：9.3

年份：2023

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：DKD; Klotho; ox-LDL deposition; Podocyte injury; IGF-1R; RAC1

摘要："ObjectiveDiabetic kidney disease (DKD) is characterized by the abnormal deposition of oxidized low-density lipoprotein (ox-LDL), which contributes to podocyte damage. Klotho, an aging suppressor that plays a critical role in protecting podocytes in DKD, is mainly expressed in kidney tubular epithelium and secreted in the blood. However, it has not been established whether Klotho can alleviate podocyte injury by inhibiting renal ox-LDL deposition, and the potential molecular mechanisms require further investigation.MethodsWe conducted a comprehensive analysis of serum and kidney biopsy samples obtained from patients diagnosed with DKD. Additionally, to explore the underlying mechanism of Klotho in the deposition of ox-LDL in the kidneys, we employed a mouse model of DKD with the Klotho genotype induced by streptozotocin (STZ). Furthermore, we conducted meticulous in vitro experiments on podocytes to gain further insights into the specific role of Klotho in the deposition of ox-LDL within the kidney.ResultsOur groundbreaking study unveiled the remarkable ability of the soluble form of Klotho to effectively inhibit high glucose-induced ox-LDL deposition in podocytes affected by DKD. Subsequent investigations elucidated that Klotho achieved this inhibition by reducing the expression of the insulin/insulin-like growth factor 1 receptor (IGF-1R), consequently leading to a decrease in the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) and an enhancement of mitochondrial function. Ultimately, this series of events culminated in a significant reduction in the expression of the oxidized low-density lipoprotein receptor (OLR1), thereby resulting in a notable decrease in renal ox-LDL deposition in DKD.ConclusionOur findings suggested that Klotho had the potential to mitigate podocyte injury and reduced high glucose-induced ox-LDL deposition in glomerulus by modulating the IGF-1R/RAC1/OLR1 signaling. These results provided valuable insights that could inform the development of novel strategies for diagnosing and treating DKD."

基金机构："Special thanks to the Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, P.R China for assistance in performing kidney biopsies and providing clinical data. Thanks to urology and nephropathy center of the Seco; urology and nephropathy center of the Second Affiliated Hospital of Chongqing Medical University"

基金资助正文："Special thanks to the Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, P.R China for assistance in performing kidney biopsies and providing clinical data. Thanks to urology and nephropathy center of the Second Affiliated Hospital of Chongqing Medical University for providing adjacent normal kidney tissue samples."