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ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease

  • Author Footnotes
    1 Contribute equally to this study as co-first author.
    Junlin Zhang
    Footnotes
    1 Contribute equally to this study as co-first author.
    Affiliations
    Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China

    Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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  • Author Footnotes
    1 Contribute equally to this study as co-first author.
    Yucheng Wu
    Footnotes
    1 Contribute equally to this study as co-first author.
    Affiliations
    Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China

    Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
    Search for articles by this author
  • Jie Zhang
    Affiliations
    Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
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  • Rui Zhang
    Affiliations
    Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China

    Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
    Search for articles by this author
  • Yiting Wang
    Affiliations
    Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China

    Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
    Search for articles by this author
  • Fang Liu
    Correspondence
    Corresponding author at: Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu 610041, Sichuan, China.
    Affiliations
    Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China

    Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
    Search for articles by this author
  • Author Footnotes
    1 Contribute equally to this study as co-first author.
Published:December 12, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155377

      Highlights

      • We and others’ previous work led us to hypothesize that ABCA1 dysfunction could aggravate the renal injury in DM.
      • In this study, we generated a DM-ABCA1-/- mouse model to investigate the role of ABCA1 in GECs injury for the first time in DM.
      • ABCA1 deficiency contributed to inflammatory injury and apoptosis of GECs through endoplasmic reticulum stress in DM.
      • ABCA1 maybe a potential effective therapeutic target for early DKD progression.

      Abstract

      Background

      Hyperglycemia and dyslipidemia are two major characteristics of diabetes. In this study, the effects of glomerular cholesterol accumulation primarily due to ABCA1 deficiency on glomerular endothelial injury in diabetic kidney disease (DKD) and the possible mechanisms were investigated.

      Methods

      The effects of ABCA1 deficiency on glomerular lipid deposition and kidney injury were examined in a type 2 diabetic mouse model with ABCA1 deficiency in glomerular endothelial cells (DM-ABCA1−/− mice) and human renal glomerular endothelial cells (HRGECs) cultured in high glucose and high cholesterol conditions, which simulated type 2 diabetes in vitro.

      Results

      ABCA1 deficiency in glomerular endothelial cells exacerbated renal lipid deposition and kidney injuries in type 2 diabetic mice and manifested as increased creatinine levels, more severe proteinuria, mesangial matrix expansion and fusion of foot processes, and more pronounced renal inflammatory injury and cell death. In HRGECs cultured under high glucose and high cholesterol conditions, ABCA1 deficiency increased the deposition of cellular cholesterol, contributed to inflammation and apoptosis, damaged the endothelial glycocalyx barrier, and induced endoplasmic reticulum stress (ERS). Conversely, ABCA1 overexpression enhancing cholesterol efflux or inhibition of ERS in vitro, significantly protected against glomerular endothelial injury stimulated by high glucose and high cholesterol.

      Conclusions

      These findings establish a pathogenic role of ABCA1 deficiency in glomerular endothelium injury and dysfunction and imply that ABCA1 may represent a potential effective therapeutic target for early diabetic kidney disease.

      Graphical abstract

      Keywords

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      References

      1. Diabetes around the world in 2021. The IDF Diabetes Atlas 10th Edition[Internet] ed: International Diabetes Federation. p. Available from https://diabetesatlas.org/.

        • Ruiz-Ortega M.
        • Rodrigues-Diez R.R.
        • Lavoz C.
        • et al.
        Special issue "Diabetic nephropathy: diagnosis, prevention and treatment".
        J Clin Med. 2020; 9https://doi.org/10.3390/jcm9030813
        • Alicic R.Z.
        • Rooney M.T.
        • Tuttle K.R.
        Diabetic kidney disease: challenges, progress, and possibilities.
        ClinJAmSocNephrol. 2017; 12: 2032-2045https://doi.org/10.2215/CJN.11491116
        • Korakas E.
        • Ikonomidis I.
        • Markakis K.
        • et al.
        The endothelial glycocalyx as a key mediator of albumin handling and the development of diabetic nephropathy.
        Curr Vasc Pharmacol. 2020; 18: 619-631https://doi.org/10.2174/157016111866619122412 0242
        • Amirpour-Najafabadi B.
        • Hosseini S.S.
        • Sam-Sani P.
        • et al.
        The glycocalyx, a novel key in understanding of mechanism of diabetic nephropathy: a commentary.
        J Diabetes Metab Disord. 2021; 20: 2049-2053https://doi.org/10.1007/s40200-021-00826-y
        • Dane M.J.
        • van den Berg B.M.
        • Avramut M.C.
        • et al.
        Glomerular endothelial surface layer acts as a barrier against albumin filtration.
        Am J Pathol. 2013; 182: 1532-1540https://doi.org/10.1016/j.ajpath.2013.01.049
        • Salmon A.
        • Ferguson J.
        • Burford J.
        • et al.
        Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction.
        JAmSocNephrol. 2012; 23: 1339-1350https://doi.org/10.1681/ASN.2012010017
        • Fridén V.
        • Oveland E.
        • Tenstad O.
        • et al.
        The glomerular endothelial cell coat is essential for glomerular filtration.
        Kidney Int. 2011; 79: 1322-1330https://doi.org/10.1038/ki.2011.58
        • Liu Y.
        • Xiang H.
        • Xiong W.
        • et al.
        Glucolipotoxicity induces endothelial cell dysfunction by activating autophagy and inhibiting autophagic flow.
        Diab Vasc Dis Res. 2022; 19 (14791641221102513-14791641221102513)https://doi.org/10.1177/1479164122110 2513
        • Yin Q.H.
        • Zhang R.
        • Li L.
        • et al.
        Exendin-4 ameliorates lipotoxicity-induced glomerular endothelial cell injury by improving ABC transporter A1-mediated cholesterol efflux in diabetic apoE knockout mice.
        J Biol Chem. 2016; 291: 26487-26501https://doi.org/10.1074/jbc.M116.730564
        • Fadini G.P.
        • Avogaro A.
        Potential manipulation of endothelial progenitor cells in diabetes and its complications.
        Diabetes Obes Metab. 2010; 12: 570-583https://doi.org/10.1111/j.1463-1326.2010.01210.x
        • Chen P.
        • Liu H.
        • Xiang H.
        • et al.
        Palmitic acid-induced autophagy increases reactive oxygen species via the Ca(2+)/PKCα/NOX4 pathway and impairs endothelial function in human umbilical vein endothelial cells.
        Exp Ther Med. 2019; 17: 2425-2432https://doi.org/10.3892/etm.2019.7269
        • Zhao Q.
        • Yang H.
        • Liu F.
        • et al.
        Naringenin exerts cardiovascular protective effect in a palmitate-induced human umbilical vein endothelial cell injury model via autophagy flux improvement.
        Mol Nutr Food Res. 2019; 63e1900601https://doi.org/10.1002/mnfr.201900601
        • Oram J.F.
        • Lawn R.M.
        ABCA1. The gatekeeper for eliminating excess tissue cholesterol.
        J Lipid Res. 2001; 42: 1173-1179
        • Herman-Edelstein M.
        • Scherzer P.
        • Tobar A.
        • et al.
        Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy.
        J Lipid Res. 2014; 55: 561-572https://doi.org/10.1194/jlr.P040501
        • Lee H.S.
        • Kruth H.S.
        Accumulation of cholesterol in the lesions of focal segmental glomerulosclerosis.
        Nephrology (Carlton). 2003; 8 (224-223)https://doi.org/10.1046/j.1440-1797.2003.00160.x
        • Timmins J.M.
        • Lee J.Y.
        • Boudyguina E.
        • et al.
        Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.
        J Clin Invest. 2005; 115: 1333-1342https://doi.org/10.1172/JCI23915
        • Kisanuki Y.Y.
        • Hammer R.E.
        • Miyazaki J.
        • et al.
        Tie2-cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo.
        Dev Biol. 2001; 230: 230-242https://doi.org/10.1006/dbio.2000.0106
        • Lu X.
        • Xuan W.
        • Li J.
        • et al.
        AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy.
        Autophagy. 2021; 17: 3622-3643https://doi.org/10.1080/15548627.2021.1886829
        • Wu J.
        • Zhang F.
        • Ruan H.
        • et al.
        Integrating network pharmacology and RT-qPCR analysis to investigate the mechanisms underlying ZeXie decoction-mediated treatment of non-alcoholic fatty liver disease.
        Front Pharmacol. 2021; 12 (722016-722016)https://doi.org/10.3389/fphar.2021.722016
        • Zhang W.
        • Gao J.
        • Shen F.
        • et al.
        Cinnamaldehyde changes the dynamic balance of glucose metabolism by targeting ENO1.
        Life Sci. 2020; 258118151https://doi.org/10.1016/j.lfs.2020.118151
        • Liao Y.
        • Xia X.
        • Liu N.
        • et al.
        Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination.
        Oncogene. 2018; 37: 1896-1910https://doi.org/10.1038/s41388-017-0069-z
        • Fu J.
        • Wei C.
        • Zhang W.
        • et al.
        Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice.
        Kidney Int. 2018; 94: 326-345https://doi.org/10.1016/j.kint.2018.02.028
        • Li L.
        • Yin Q.
        • Tang X.
        • et al.
        C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway.
        PloS one. 2014; 9e113639https://doi.org/10.1371/journal.pone.0113639
        • Ducasa G.M.
        • Mitrofanova A.
        • Mallela S.K.
        • et al.
        ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes.
        J Clin Invest. 2019; 129: 3387-3400https://doi.org/10.1172/JCI125316
        • Zhang K.
        • Kaufman R.J.
        Unfolding the toxicity of cholesterol.
        Nat Cell Biol. 2003; 5: 769-770https://doi.org/10.1038/ncb0903-769
        • Ruan X.Z.
        • Varghese Z.
        • Moorhead J.F.
        An update on the lipid nephrotoxicity hypothesis.
        Nat Rev Nephrol. 2009; 5: 713-721https://doi.org/10.1038/nrneph.2009.184
        • Hiruma S.
        • Shigiyama F.
        • Hisatake S.
        • et al.
        A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study.
        Cardiovasc Diabetol. 2021; 20: 32https://doi.org/10.1186/s12933-021-01228-3
        • Shaman A.M.
        • Bain S.C.
        • Bakris G.L.
        • et al.
        Effect of the glucagon-like Peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: a pooled analysis of SUSTAIN 6 and LEADER trials.
        Circulation. 2021; https://doi.org/10.1161/CIRCULATIONAHA.121.055459
        • Mitrofanova A.
        • Molina J.
        • Varona Santos J.
        • et al.
        Hydroxypropyl-β-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis.
        Kidney Int. 2018; 94: 1151-1159https://doi.org/10.1016/j.kint.2018.06.031
        • Druilhet R.E.
        • Overturf M.L.
        • Kirkendall W.M.
        Cortical and medullary lipids of normal and nephrosclerotic human kidney.
        Int J Biochem. 1978; 9: 729-734https://doi.org/10.1016/0020-711x(78)90040-x
        • Merscher-Gomez S.
        • Guzman J.
        • Pedigo C.E.
        • et al.
        Cyclodextrin protects podocytes in diabetic kidney disease.
        Diabetes. 2013; 62: 3817-3827https://doi.org/10.2337/db13-0399
        • Patel M.
        • Wang X.X.
        • Magomedova L.
        • et al.
        Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice.
        Diabetologia. 2014; 57: 435-446https://doi.org/10.1007/s00125-013-3095-6
        • Fligny C.
        • Barton M.
        • Tharaux P.L.
        Endothelin and podocyte injury in chronic kidney disease.
        Contrib Nephrol. 2011; 172: 120-138https://doi.org/10.1159/000328692
        • Dhaun N.
        • Goddard J.
        • Kohan D.E.
        • et al.
        Role of endothelin-1 in clinical hypertension: 20 years on.
        Hypertension. 2008; 52 (Dallas, Tex: 1979): 452-459https://doi.org/10.1161/HYPERTENSIONAHA.108.117366
        • Lenoir O.
        • Milon M.
        • Virsolvy A.
        • et al.
        Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.
        JAmSocNephrol. 2014; 25: 1050-1062https://doi.org/10.1681/ASN.2013020195
        • Boels M.G.
        • Avramut M.C.
        • Koudijs A.
        • et al.
        Atrasentan reduces albuminuria by restoring the glomerular endothelial glycocalyx barrier in diabetic nephropathy.
        Diabetes. 2016; 65: 2429-2439https://doi.org/10.2337/db15-1413
        • Tabas I.
        Consequences of cellular cholesterol accumulation: basic concepts and physiological implications.
        J Clin Invest. 2002; 110: 905-911https://doi.org/10.1172/JCI16452
        • Feng B.
        • Yao P.M.
        • Li Y.
        • et al.
        The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages.
        Nat Cell Biol. 2003; 5: 781-792https://doi.org/10.1038/ncb1035
        • Song Y.
        • Liu J.
        • Zhao K.
        • et al.
        Cholesterol-induced toxicity: an integrated view of the role of cholesterol in multiple diseases.
        Cell Metab. 2021; 33: 1911-1925https://doi.org/10.1016/j.cmet.2021.09.001
        • Ni L.
        • Yuan C.
        • Wu X.
        Endoplasmic reticulum stress in diabetic nephrology: regulation, pathological role, and therapeutic potential.
        Oxid Med Cell Longev. 2021; 2021: 7277966https://doi.org/10.1155/2021/7277966
        • Sozen E.
        • Ozer N.K.
        Impact of high cholesterol and endoplasmic reticulum stress on metabolic diseases: an updated mini-review.
        Redox Biol. 2017; 12: 456-461https://doi.org/10.1016/j.redox.2017.02.025
        • Zhang K.
        • Kaufman R.J.
        From endoplasmic-reticulum stress to the inflammatory response.
        Nature. 2008; 454: 455-462https://doi.org/10.1038/nature07203
        • Sano R.
        • Reed J.C.
        ER stress-induced cell death mechanisms.
        Biochim Biophys Acta. 2013; 1833: 3460-3470https://doi.org/10.1016/j.bbamcr.2013.06.028
        • Qiu Z.L.
        • Zhang J.P.
        • Guo X.C.
        Endoplasmic reticulum stress and vascular endothelial cell apoptosis.
        Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2014; 36: 102-107https://doi.org/10.3881/j.issn.1000-503X.2014.01.019
        • Wright M.B.
        • Varona Santos J.
        • Kemmer C.
        • et al.
        Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease.
        Nat Commun. 2021; 12: 4662https://doi.org/10.1038/s41467-021-24890-3
        • Wang L.
        • Wesemann S.
        • Krenn L.
        • et al.
        Erythrodiol, an olive oil constituent, increases the half-life of ABCA1 and enhances cholesterol efflux from THP-1-derived macrophages.
        Front Pharmacol. 2017; 8: 375https://doi.org/10.3389/fphar.2017.00375
        • Liu P.
        • Peng L.
        • Zhang H.
        • et al.
        Tangshen formula attenuates diabetic nephropathy by promoting ABCA1-mediated renal cholesterol efflux in db/db mice.
        Front Physiol. 2018; 9: 343https://doi.org/10.3389/fphys.2018.00343
        • Kang Y.S.
        • Lee M.H.
        • Song H.K.
        • et al.
        Chronic administration of visfatin ameliorated diabetic nephropathy in type 2 diabetic mice.
        Kidney Blood Press Res. 2016; 41: 311-324https://doi.org/10.1159/000443433
        • Terasaka N.
        • Hiroshima A.
        • Koieyama T.
        • et al.
        T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice.
        FEBS Lett. 2003; 536: 6-11https://doi.org/10.1016/s0014-5793(02)03578-0
        • Caldas Y.A.
        • Giral H.
        • Cortázar M.A.
        • et al.
        Liver X receptor-activating ligands modulate renal and intestinal sodium-phosphate transporters.
        Kidney Int. 2011; 80: 535-544https://doi.org/10.1038/ki.2011.159
        • Kiss E.
        • Kränzlin B.
        • Wagenblaβ K.
        • et al.
        Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: prevention by liver X receptors.
        Am J Pathol. 2013; 182: 727-741https://doi.org/10.1016/j.ajpath.2012.11.033