{
    "abstract": "Lipotoxicity has been implicated in diabetic kidney disease (DKD). However, the role of high glucose levels in DKD and the underlying renal protective mechanisms of GLP-1 receptor agonists (GLP-1RAs) remain unclear.\nTo investigate cholesterol accumulation, pyroptosis in glomerular endothelial cells (GEnCs), and the renal protective mechanisms of GLP-1RAs, we used various techniques, including RT-qPCR, Oil Red O staining, Western blotting, lactate dehydrogenase (LDH) activity assays, circRNA microarrays, bioinformatics analysis, gain and loss-of-function experiments, rescue experiments, and luciferase assays. Additionally, in vivo experiments were conducted using C57BL/6J and ApoE-deficient (ApoE-/-) mice.\nGEnCs exposed to high glucose exhibited reduced cholesterol efflux, which was accompanied by downregulation of ATP-binding cassette transporter A1 (ABCA1) expression, cholesterol accumulation, and pyroptosis. Circ8411 was identified as a regulator of ABCA1, inhibiting miR-23a-5p through its binding to the 3'UTR. Additionally, higher glucose levels decreased circ8411 expression by inhibiting RXR\u03b1. GLP-1RAs effectively reduced cholesterol accumulation and cell pyroptosis by targeting the RXR\u03b1/circ8411/miR-23a-5p/ABCA1 pathway. In diabetic ApoE-/- mice, renal structure and function were impaired, with resulted in increased cholesterol accumulation and pyroptosis; however, GLP-1RAs treatment reversed these detrimental changes.\nThese findings suggest that the RXR\u03b1/circ8411/miR-23a-5p/ABCA1 pathway mediates the contribution of high glucose to lipotoxic renal injury. Targeting this pathway may represent a potential therapeutic strategy for patients with DKD and hypercholesterolemia. Moreover, GLP-1RAs may provide renal protective effects by activating this pathway.",
    "authors": [
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Weixi",
            "initials": "W",
            "lastname": "Wu"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Yao",
            "initials": "Y",
            "lastname": "Wang"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Xian",
            "initials": "X",
            "lastname": "Shao"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Shuai",
            "initials": "S",
            "lastname": "Huang"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Jian",
            "initials": "J",
            "lastname": "Wang"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Saijun",
            "initials": "S",
            "lastname": "Zhou"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Hongyan",
            "initials": "H",
            "lastname": "Liu"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Yao",
            "initials": "Y",
            "lastname": "Lin"
        },
        {
            "affiliation": "NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.\nTianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.",
            "firstname": "Pei",
            "initials": "P",
            "lastname": "Yu"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright: \u00a9 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
    "doi": "10.1371/journal.pone.0314628\n10.1016/j.kint.2022.08.012\n10.3389/fendo.2021.672350\n10.1155/2018/7078214\n10.7150/ijbs.64665\n10.1016/j.metabol.2022.155377\n10.3390/ijms21072632\n10.1016/j.amjms.2019.11.004\n10.1016/j.phymed.2018.01.026\n10.3389/fphys.2017.00519\n10.1146/annurev-immunol-101220-030653\n10.1007/s12079-021-00664-w\n10.2337/db16-0695\n10.2174/0929867324666170705124647\n10.1016/j.vph.2015.07.004\n10.1016/j.freeradbiomed.2016.03.035\n10.1016/j.pharmthera.2020.107514\n10.3390/biom11121769\n10.1161/CIRCRESAHA.120.317178\n10.1038/s41467-022-32437-3\n10.1038/s41467-021-24890-3\n10.3389/fphys.2018.00343\n10.3389/fphys.2020.552483\n10.1016/j.cell.2022.04.021\n10.7150/thno.42174\n10.1016/j.tibs.2021.11.004\n10.1016/j.pharmthera.2022.108270\n10.1074/jbc.M116.730564\n10.1210/en.2013-1934\n10.1172/jci.insight.136845\n10.1016/j.cca.2017.11.005\n10.1002/jcp.30200\n10.1002/jcp.26959\n10.1016/j.yjmcc.2018.09.004\n10.1158/0008-5472.CAN-17-3009\n10.1016/j.cell.2014.03.012\n10.1038/ki.2013.427\n10.1016/j.peptides.2013.12.015\n10.1007/s00125-011-2241-2",
    "journal": "PloS one",
    "keywords": [],
    "methods": null,
    "publication_date": "2024-12-02",
    "pubmed_id": "39621727\n36202661\n34276558\n29675433\n34975320\n36521550\n32290082\n32039770\n29519318\n28790925\n35080918\n35041192\n27899487\n28685678\n26187353\n27038735\n32105674\n34944413\n32819213\n35974019\n34341345\n29681863\n33192550\n35584701\n32206104\n34865956\n36002078\n27784780\n24467746\n32614804\n29129476\n33275299\n30054916\n30227118\n29844124\n24679540\n24152968\n24418070\n21786155",
    "results": "GEnCs exposed to high glucose exhibited reduced cholesterol efflux, which was accompanied by downregulation of ATP-binding cassette transporter A1 (ABCA1) expression, cholesterol accumulation, and pyroptosis. Circ8411 was identified as a regulator of ABCA1, inhibiting miR-23a-5p through its binding to the 3'UTR. Additionally, higher glucose levels decreased circ8411 expression by inhibiting RXR\u03b1. GLP-1RAs effectively reduced cholesterol accumulation and cell pyroptosis by targeting the RXR\u03b1/circ8411/miR-23a-5p/ABCA1 pathway. In diabetic ApoE-/- mice, renal structure and function were impaired, with resulted in increased cholesterol accumulation and pyroptosis; however, GLP-1RAs treatment reversed these detrimental changes.",
    "title": "GLP-1RA improves diabetic renal injury by alleviating glomerular endothelial cells pyrotosis via RXR\u03b1/circ8411/miR-23a-5p/ABCA1 pathway.",
    "xml": "<Element 'PubmedArticle' at 0x788504443c40>"
}