CD36：a New Therapeutic Target for Chronic Kidney Disease

doi:10.12114/j.issn.1007-9572.2019.00.228

Abstract

Abstract: The transmembrane glycoprotein receptor CD36 binds to ligands participating in various physiological and pathological processes in the body.The recent studies found increased expression of CD36 in chronic kidney disease（CKD）．To introduce the structure，function and expression regulation of CD36，this article described the related mechanism of CD36 in CKD by summarizing the domestic and foreign literatures as well as previous studies.It came to the conclusions that CD36 promoted the progress of CKD in four aspects that included renal lipid deposition，lipid peroxidation，a variety of material endocytosis and intracellular/external cell signal transduction.At the same time，this article pointed out the feasibility of soluble CD36 as a biomarker for detecting the development of CKD，and prospected for drug therapy of CKD in order to provide a new direction for the diagnosis and treatment of CKD.

Key words: Kidney diseases, Chronic disease, CD36, Chronic kidney disease, Therapy, Target

摘要： CD36是一种细胞表面跨膜糖蛋白受体，与配体结合参与机体多种生理病理过程。近年来研究发现CD36在慢性肾脏病（CKD）中表达增加。本文首先介绍了CD36的结构功能及其表达调控，通过总结国内外文献，并结合前期的研究基础，叙述了CD36在CKD发病中的相关作用机制，得出CD36通过介导肾脏脂质沉积、脂质过氧化、肾脏细胞对多种物质的内吞及细胞内/外信号转导，促进CKD的进展。同时指出可溶性CD36作为CKD进展的生物标志物的可行性，并对CKD药物治疗的研发进行了展望，以期为CKD的诊治提供新的方向。

关键词: 肾疾病, 慢性病, CD36, 慢性肾脏病, 治疗, 靶点

HOU Yanjuan,WANG Lihua,WANG Qian. CD36：a New Therapeutic Target for Chronic Kidney Disease　[J]. Chinese General Practice, 2019, 22(30): 3768-3773. DOI: 10.12114/j.issn.1007-9572.2019.00.228.
侯延娟,王利华,王倩. CD36：慢性肾脏病治疗的新靶点[J]. 中国全科医学, 2019, 22(30): 3768-3773. DOI: 10.12114/j.issn.1007-9572.2019.00.228.

References

［1］ZHAO L，VARGHESE Z，MOORHEAD J F，et al．CD36 and lipid metabolism in the evolution of atherosclerosis［J］．Br Med Bull，2018，126（1）：101-112．DOI：10.1093/bmb/ldy006.
［2］KANG H M，AHN S H，CHOI P，et al．Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development［J］．Nat Med，2015，21（1）：37-46．DOI：10.1038/nm.3762.
［3］HUA W，HUANG H Z，TAN L T，et al．CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress［J］．PLoS One，2015，10（5）：e0127507．DOI：10.1371/journal.pone.0127507.
［4］彭隽，贾汝汉，党建中，等．CD36在高糖诱导的大鼠肾小球系膜细胞凋亡中的作用及机制［J］．中华肾脏病杂志，2014，30（5）：370-376．DOI：10.3760/cma.j.issn.1001-7097.2014.05.009.
PENG J，JIA R H，DANG J Z，et al．The effects and underlying mechanism of CD36 in high glucose-induced rat glomerular mesangial cells apoptosis［J］．Chinese Journal of Nephrology，2014，30（5）：370-376．DOI：10.3760/cma.j.issn.1001-7097.2014.05.009.
［5］PENNATHUR S，PASICHNYK K，BAHRAMI N M，et al．The macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury［J］．Am J Pathol，2015，185（8）：2232-2245．DOI：10.1016/j.ajpath.2015.04.016.
［6］YANG X C，OKAMURA D M，LU X F，et al．CD36 in chronic kidney disease：novel insights and therapeutic opportunities［J］．Nat Rev Nephrol，2017，13（12）：769-781．DOI：10.1038/nrneph.2017.126.
［7］NECULAI D，SCHWAKE M，RAVICHANDRAN M，et al．Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36［J］．Nature，2013，504（7478）：172-176．DOI：10.1038/nature12684.
［8］CHOROMANSKA B，MYSLIWIEC P，CHOROMANSKA K，et al．The role of CD36 receptor in the pathogenesis of atherosclerosis［J］．Adv Clin Exp Med，2017，26（4）：717-722．DOI：10.17219/acem/62325.
［9］QIAO L P，ZOU C H，SHAO P，et al．Transcriptional regulation of fatty acid Translocase/CD36 expression by CCAAT/enhancer-binding protein alpha［J］．J Biol Chem，2008，283（14）：8788-8795．DOI：10.1074/jbc.M800055200.
［10］GOTO K，ISO T，HANAOKA H，et al．Peroxisome proliferator-activated receptor-γ in capillary endothelia promotes fatty acid uptake by heart during long-term fasting［J］．J Am Heart Assoc，2013，2（1）：e004861．DOI：10.1161/JAHA.112.004861.
［11］FENG L，GU C W，LI Y X，et al．High glucose promotes CD36 expression by upregulating peroxisome proliferator-activated receptor γ levels to exacerbate lipid deposition in renal tubular cells［J］．Biomed Res Int，2017，2017：1414070．DOI：10.1155/2017/1414070.
［12］BABAAHMADI REZAEI H，DOOSTI M，AMINIAN M，et al．Compare the effect of eicosapentaenoic acid and oxidized low-density lipoprotein on the expression of CD36 and peroxisome proliferator-activated receptor gamma［J］．Iran Biomed J，2013，17（2）：84-92.
［13］CHABOWSKI A，COORT S L，CALLES-ESCANDON J，et al．Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm［J］．Am J Physiol Endocrinol Metab，2004，287（4）：E781-E789．DOI：10.1152/ajpendo.00573.2003.
［14］王一婷，郭睿坤，李治成，等．血清可溶性CD36与慢性肾脏病合并糖尿病患者临床指标的关系［J］．四川大学学报：医学版，2018，49（3）：414-419．DOI：10.13464/j.scuxbyxb.2018.03.020.
WANG Y T，GUO R K，LI Z C，et al．Association of serum soluble CD36 with clinical variables in diabetic patients with chronic kidney diseas［J］．Journal of Sichuan University：Medical Science Edition，2018，49（3）：414-419．DOI：10.13464/j.scuxbyxb.2018.03.020.
［15］ALKHATATBEH M J，MHAIDAT N M，ENJETI A K，et al．The putative diabetic plasma marker，soluble CD36，is non-cleaved，non-soluble and entirely associated with microparticles［J］．J Thromb Haemost，2011，9（4）：844-851．DOI：10.1111/j.1538-7836.2011.04220.x.
［16］RUAN X Z，VARGHESE Z，MOORHEAD J F.An update on the lipid nephrotoxicity hypothesis［J］．Nat Rev Nephrol，2009，5（12）：713-721．DOI：10.1038/nrneph.2009.184.
［17］MEYER C，NADKARNI V，STUMVOLL M，et al．Human kidney free fatty acid and glucose uptake：evidence for a renal glucose-fatty acid cycle［J］．Am J Physiol，1997，273（3 Pt 1）：E650-654．DOI：10.1152/ajpendo.1997.273.3.E650.
［18］HERMAN-EDELSTEIN M，SCHERZER P，TOBAR A，et al．Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy［J］．J Lipid Res，2014，55（3）：561-572．DOI：10.1194/jlr.P040501.
［19］OKAMURA D M，PENNATHUR S，PASICHNYK K，et al．CD36 regulates oxidative stress and inflammation in hypercholesterolemic CKD［J］．J Am Soc Nephrol，2009，20（3）：495-505．DOI：10.1681/ASN.2008010009.
［20］龙香菊，孙亚楠，刘喆，等．Ox-LDL受体CD36与糖尿病大鼠肾小管损伤的关系［J］．中华内分泌代谢杂志，2016，32（7）：602-606．DOI：10.3760/cma.j.issn.1000-6699.2016.07.015.
［21］HOU Y J，SHI Y H，HAN B S，et al．The antioxidant peptide SS31 prevents oxidative stress，downregulates CD36 and improves renal function in diabetic nephropathy［J］．Nephrol Dial Transplant，2018，33（11）：1908-1918．DOI：10.1093/ndt/gfy021.
［22］KENNEDY D J，CHEN Y L，HUANG W X，et al．CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney［J］．Hypertension，2013，61（1）：216-224．DOI：10.1161/HYPERTENSIONAHA.112.198770.
［23］SHEEDY F J，GREBE A，RAYNER K J，et al．CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation［J］．Nat Immunol，2013，14（8）：812-820．DOI：10.1038/ni.2639.
［24］TSUMURA M，KINOUCHI T，ONO S，et al．Serum lipid metabolism abnormalities and change in lipoprotein contents in patients with advanced-stage renal disease［J］．Clin Chim Acta，2001，314（1/2）：27-37.
［25］GAO X，WU J X，QIAN Y X，et al．Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36［J］．Int J Mol Med，2014，34（2）：564-572．DOI：10.3892/ijmm.2014.1799.
［26］DESCAMPS-LATSCHA B，WITKO-SARSAT V，NGUYEN-KHOA T，et al．Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients［J］．Am J Kidney Dis，2005，45（1）：39-47.
［27］IWAO Y，NAKAJOU K，NAGAI R，et al．CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products［J］．Am J Physiol Renal Physiol，2008，295（6）：F1871-1880．DOI：10.1152/ajprenal.00013.2008.
［28］CAO W，XU J，ZHOU Z M，et al．Advanced oxidation protein products activate intrarenal renin-angiotensin system via a CD36-mediated，redox-dependent pathway［J］．Antioxid Redox Signal，2013，18（1）：19-35．DOI：10.1089/ars.2012.4603.
［29］OHGAMI N，NAGAI R，IKEMOTO M，et al．CD36，a member of the class b scavenger receptor family，as a receptor for advanced glycation end products［J］．J Biol Chem，2001，276（5）：3195-3202．DOI：10.1074/jbc.M006545200.
［30］XANTHIS A，HATZITOLIOS A，FIDANI S，et al．Receptor of advanced glycation end products（RAGE）positively regulates CD36 expression and reactive oxygen species production in human monocytes in diabetes［J］．Angiology，2009，60（6）：772-779．DOI：10.1177/0003319708328569.
［31］HODGKINSON C P，LAXTON R C，PATEL K，et al．Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis［J］．Arterioscler Thromb Vasc Biol，2008，28（12）：2275-2281．DOI：10.1161/ATVBAHA.108.175992.
［32］SUSZTAK K，CICCONE E，MCCUE P，et al．Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy［J］．PLoS Med，2005，2（2）：e45．DOI：10.1371/journal.pmed.0020045.
［33］GEORGIOU D K，DAGNINO-ACOSTA A，LEE C S，et al．Ca2+ Binding/Permeation via calcium channel，CaV1.1，regulates the intracellular distribution of the fatty acid transport protein，CD36，and fatty acid metabolism［J］．J Biol Chem，2015，290（39）：23751-23765．DOI：10.1074/jbc.M115.643544.
［34］HOU Y J，WU M，WEI J Y，et al．CD36 is involved in high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells［J］．Biochem Biophys Res Commun，2015，468（1/2）：281-286．DOI：10.1016/j.bbrc.2015.10.112.
［35］SEIMON T A，NADOLSKI M J，LIAO X H，et al．Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress［J］．Cell Metab，2010，12（5）：467-482．DOI：10.1016/j.cmet.2010.09.010.
［36］BROWN P M，KENNEDY D J，MORTON R E，et al．CD36/SR-B2-TLR2 dependent pathways enhance porphyromonas gingivalis mediated atherosclerosis in the ldlr KO mouse model［J］．PLoS One，2015，10（5）：e0125126．DOI：10.1371/journal.pone.0125126.
［37］HANDBERG A，H?JLUND K，GASTALDELLI A，et al．Plasma sCD36 is associated with markers of atherosclerosis，insulin resistance and fatty liver in a nondiabetic healthy population［J］．J Intern Med，2012，271（3）：294-304．DOI：10.1111/j.1365-2796.2011.02442.x.
［38］CHMIELEWSKI M，BRAGFORS-HELIN A C，STENVINKEL P，et al．Serum soluble CD36，assessed by a novel monoclonal antibody-based sandwich ELISA，predicts cardiovascular mortality in dialysis patients［J］．Clin Chim Acta，2010，411（23/24）：2079-2082．DOI：10.1016/j.cca.2010.09.009.
［39］SHIJU T M，MOHAN V，BALASUBRAMANYAM M，et al．Soluble CD36 in plasma and urine：a plausible prognostic marker for diabetic nephropathy［J］．J Diabetes Complicat，2015，29（3）：400-406．DOI：10.1016/j.jdiacomp.2014.12.012.
［40］LYKKEBOE S，LARSEN A L，HANDBERG A. Lack of consistency between two commercial ELISAs and against an in-house ELISA for the detection of CD36 in human plasma［J］Clin Chem Lab Med，2012，50（6）： 1071-1074．DOI：10.1515/cclm-2011-0950.
［41］YOKOI H，YANAGITA M.Targeting the fatty acid transport protein CD36，a class B scavenger receptor，in the treatment of renal disease［J］．Kidney Int，2016，89（4）：740-742．DOI：10.1016/j.kint.2016.01.009.
［42］BAINES R J，CHANA R S，HALL M，et al．CD36 mediates proximal tubular binding and uptake of albumin and is upregulated in proteinuric nephropathies［J］．Am J Physiol Renal Physiol，2012，303（7）：F1006-1014．DOI：10.1152/ajprenal.00021.2012.
［43］HUA W，HUANG H Z，TAN L T，et al．CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress［J］．PLoS One，2015，10（5）：e0127507．DOI：10.1371/journal.pone.0127507.
［44］SOUZA A C，BOCHAROV A V，BARANOVA I N，et al．Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation［J］．Kidney Int，2016，89（4）：809-822．DOI：10.1016/j.kint.2015.12.043.
［45］BOCHAROV A V，WU T H，BARANOVA I N，et al．Synthetic amphipathic helical peptides targeting CD36 attenuate lipopolysaccharide-induced inflammation and acute lung injury［J］．J Immunol，2016，197（2）：611-619．DOI：10.4049/jimmunol.1401028.
［46］ZHANG J Q，MULUMBA M，ONG H，et al．Diversity-oriented synthesis of cyclic azapeptides by a3 -macrocyclization provides high-affinity CD36-modulating peptidomimetics［J］．Angew Chem Int Ed Engl，2017，56（22）：6284-6288．DOI：10.1002/anie.201611685.

[1]	China Sport Science Society. Guidelines for Exercise Prescription of Dyslipidemia [J]. Chinese General Practice, 2026, 29(32): 4673-4689.
[2]	ZHANG Chu, KONG Weimin, DENG Boer. Advances in Pharmacological Treatment of Recurrent or Metastatic Cervical Cancer [J]. Chinese General Practice, 2026, 29(32): 4815-4820.
[3]	KUANG Li, DING Xinxin, MA Yuanzhu. Application of Motivational Interviewing in Healthcare Provider-Patient Communication for Chronic Disease Management in Primary Care: from Principles to Practice [J]. Chinese General Practice, 2026, 29(31): 4536-4542.
[4]	HAN Leyang, ZHENG Huixian, TIAN Yiran, TANG Haoqing, LONG Ren, LI Daihan, LIU Xiaoyun. Measuring Integrated Services for Rural Chronic Disease Patients Based on Formative Measurement Theory [J]. Chinese General Practice, 2026, 29(31): 4543-4550.
[5]	GUO Zhihong, CHEN Yingying, LIU Dewu. Efficacy and Safety of Antibiotic Bone Cement Combined with Vacuum Sealing Drainage for Diabetic Foot: a Meta-analysis [J]. Chinese General Practice, 2026, 29(30): 4503-4512.
[6]	LI Xiling, ZHANG Fan, YANG Xinyue, YANG Heng. Application of Exercise Snacks in Chronic Disease Management: a Scoping Review [J]. Chinese General Practice, 2026, 29(30): 4472-4479.
[7]	WANG Dunjian, CHEN Yonggang, HU Bing, ZHAO Hengyi, YANG Qing. Application of Home-based Medication Therapy Management in Contracted Patients with Diabetes and Hypertension: a Randomized Controlled Trial [J]. Chinese General Practice, 2026, 29(29): 4226-4231.
[8]	ZHAO Congjuan, JIN Tiantian, LIANG Jie, WANG Beining, GAO Yan. Comparative Effectiveness of GLP-1 Receptor Agonists on Patients with Diabetic Kidney Disease: a Network Meta-analysis [J]. Chinese General Practice, 2026, 29(29): 4326-4336.
[9]	ZHANG Tianyu, CHEN Fei, LI Xin, ZHANG Jiajia, SHEN Man, ZHAN Xiaokai, TANG Ran, FAN Sibin, ZHAO Fengyi, HUANG Zhongxia. Significance of Elevated Levels of Leukocyte Immunoglobulin-like Receptor B1, CD36, and Lymphatic Enhancer Factor 1 in Patients with Myeloma [J]. Chinese General Practice, 2026, 29(29): 4272-4280.
[10]	JIANG Chen, AN Ni, XU Yunjing, NIU Shaona, LI Fengming, JIANG Liangmei. A Cross-sectional Study of Hospitalization Characteristics and Healthcare Resource Consumption of Patients with Cardiovascular-kidney-metabolic Syndrome [J]. Chinese General Practice, 2026, 29(28): 4172-4178.
[11]	SHI Li, ZHOU Zhenkun, LIU Jie, PAN Guofeng. A Randomized Controlled Trial of Sinew Meridian Theory-based Combined Acupuncture and Cupping Therapy for Postmenopausal Women with Stress Urinary Incontinence [J]. Chinese General Practice, 2026, 29(28): 4141-4146.
[12]	LU Hongrun, ZHANG Rui, ZHAO Yu, LI Jiazhen, WANG Weiqiang. Association of Cardiometabolic Comorbidity with Estimated Glomerular Filtration Rate [J]. Chinese General Practice, 2026, 29(28): 4179-4186.
[13]	FENG Yachen, LIU Lewei, XUE Jinyue, SUN Xianlin, LIU Huanzhong. Research Progress of Wearable Technology in the Diagnosis and Treatment of Mental Disorders [J]. Chinese General Practice, 2026, 29(27): 4016-4025.
[14]	CHEN Jingjing, BAI Xinyuan, SHA Huizi, SUN Yi, NI Jiayao, TONG Fan, ZOU Lu, MENG Fanyan, DU Juan. Analysis of the Efficacy and Safety of Gemcitabine plus S-1 Regimen versus S-1 Combined with Oxaliplatin and Irinotecan Regimen as Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma [J]. Chinese General Practice, 2026, 29(26): 3767-3773.
[15]	DONG Ao, ZHAO Naihui, OU Wenli, CHEN Shuohua, WANG Guodong, DAI Luyao, LIU Canzhang, WU Shouling, YANG Xiuhong. Association between Cardiometabolic Index and the Incident Chronic Kidney Disease: a Prospective Cohort Study [J]. Chinese General Practice, 2026, 29(25): 3614-3623.