目的: 研究高同型半胱氨酸血症（hyperhomocysteinemia,HHcy）诱导过敏性紫癜（Henoch-Schonlein purpura,HSP）胱硫醚-β-合酶（cystathionine -β- synthase,CBS）杂合突变（CBS+/-）小鼠足细胞损伤的作用及机制。方法: 野生型CBS（CBS+/+）小鼠及CBS+/-小鼠均采用印度墨水尾静脉注射、小麦醇溶蛋白灌胃及尾静脉注射的方式进行紫癜性肾炎（HSP nephritis,HSPN）造模,造模过程中给予常规饮食或高蛋氨酸饮食。比较各组小鼠血清同型半胱氨酸（homocysteinemia,Hcy）含量、肾脏病理改变及超微结构改变、血肌酐（Scr）、尿素氮（BUN）、24h尿蛋白、Podocin、Nephrin、Podocalyxin表达水平的差异。结果: 常规饮食CBS+/++HSPN组、高蛋氨酸饮食CBS+/++HSPN组均出现肾脏病理改变,且Scr、BUN、24h尿蛋白水平均高于常规饮食CBS+/+组,但高蛋氨酸饮食CBS+/++HSPN组的肾脏病理改变及Scr、BUN、24h尿蛋白水平与常规饮食CBS+/++HSPN组比较无显著性差异。常规饮食CBS+/-+HSPN组出现肾脏病理改变及超微结构改变,Scr、BUN、24h尿蛋白水平高于常规饮食CBS+/-组,Podocin、Nephrin、Podocalyxin的表达水平低于常规饮食CBS+/-组;与常规饮食CBS+/-+HSPN组比较,高蛋氨酸饮食CBS+/-+HSPN组的肾脏病理改变及超微结构改变加重,Hcy、Scr、BUN、24h尿蛋白水平升高,Podocin、Nephrin、Podocalyxin的表达水平降低;与高蛋氨酸饮食CBS+/-+HSPN组比较,叶酸+高蛋氨酸饮食CBS+/-+HSPN组的肾脏病理改变及超微结构改变减轻,Hcy、Scr、BUN、24h尿蛋白水平降低,Podocin、Nephrin、Podocalyxin的表达水平升高。结论: HHcy促进HSPN CBS+/-小鼠肾脏病理改变、足细胞损伤加重,抑制跨膜蛋白Podocin、Nephrin、Podocalyxin表达是可能的分子机制。
Abstract
Objective To study the effect and mechanism of homocysteinemia (HHcy) - induced podocyte injury in Henoch Schonlein purpura nephritis (HSPN) cystathionine -β- synthase (CBS) heterozygous mutation (CBS+/-) mice. Methods HSPN model was established in wild type CBS (CBS+/+) mice and CBS+/-mice, then given conventional diet or high methionine diet respectively. The levels of serum Hcy, renal pathological and ultrastructural changes, serum creatinine (Scr), blood urea nitrogen (BUN), 24-hour urinary protein, the expression of podocin, nephrin and podocalyxin were compared. Results The renal pathological changes were found in the CBS+/++HSPN group and the high methionine diet CBS+/++HSPN group, and the levels of Scr, BUN and 24h urinary protein were higher than those in the conventional diet CBS+/+ group, but there was no significant difference in the renal pathological changes, Scr, BUN and 24h urinary protein levels between the high methionine diet CBS+/++HSPN group and the conventional diet CBS+/++ HSPN group. Renal pathological and ultrastructural changes were observed in conventional diet CBS+/-+HSPN group, Scr, BUN and 24h urinary protein levels were higher than those of conventional diet CBS+/- group, the expression of podocin, nephrin and podocalyxin were lower than those of conventional diet CBS+/- group; compared with conventional diet CBS+/-+HSPN group, renal athological and ultrastructural changes aggravated, Hcy, Scr, BUN and 24h urinary protein levels increased, the expression of podocin, nephrin and podocalyxin decreased of high methionine diet CBS+/- group; compared with high methionine diet CBS+/- group, renal athological and ultrastructural changes improved, Hcy, Scr, BUN and 24h urinary protein levels decreased, the expression of podocin, nephrin and podocalyxin increased in folic acid+ high methionine diet CBS+/- group. Conclusion HHcy can promote renal pathological changes and podocyte injury in HSPN CBS+/- mice, and inhibit the expression of transmembrane proteins podocin, nephrin and podocalyxin is a possible molecular mechanism.
关键词
过敏性紫癜 /
紫癜性肾炎 /
高同型半胱氨酸血症 /
胱硫醚-β-合酶 /
足细胞损伤
Key words
Henoch Schonlein purpura /
Henoch Schonlein purpura nephritis /
hyperhomocysteinemia /
cystathionine β- synthase /
podocyte injury
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参考文献
[1] Tan J, Tang Y, Xu Y, et al.The Clinicopathological Characteristics of Henoch-Schonlein Purpura Nephritis with Presentation of Nephrotic Syndrome[J]. Kidney Blood Press Res, 2019, 44(4): 754-764.
[2] Huang X, Wu X, Le W, et al.Renal Prognosis and Related Risk Factors for Henoch-Schonlein Purpura Nephritis: A Chinese Adult Patient Cohort[J]. Sci Rep, 2018, 8(1): 5585.
[3] Moon H, Ko HJ, Kim AS.Hyperhomocysteinemia Concurrent with Metabolic Syndrome Is Independently Associated with Chronic Kidney Disease among Community-Dwelling Adults in an Urban Korean Population[J]. Int J Environ Res Public Health, 2020, 17(18): 6810.
[4] Shi W, Zhou Y, Wang H, et al.Synergistic interaction of hypertension and hyperhomocysteinemia on chronic kidney disease: Findings from the National Health and Nutrition Examination Survey 1999-2006[J]. J Clin Hypertens (Greenwich), 2019, 21(10): 1567-1577.
[5] 吴凯, 刘昆, 谢琳, 等. 高同型半胱氨酸血症诱导Cbs+/-小鼠肾损伤的作用机制[J]. 中国组织工程研究, 2021, 25(11): 1728-1732.
[6] 曹庆科, 殷文浩, 邹洪兴, 等. 儿童过敏性紫癜患者血清同型半胱氨酸与 CD62E 的检测及意义[J]. 中国皮肤性病学杂志, 2013, 27(9): 891-892+899.
[7] 任献国, 何旭, 杜丽芳, 等. 儿童紫癜性肾炎临床病理与尿Podocalyxin的关系[J]. 医学研究生学报, 2013, 26(3): 265-269.
[8] 邱成英, 邓颖云, 卢磊, 等. 紫草素对紫癜性肾炎大鼠肾脏的保护作用[J]. 中国临床药理学杂志, 2020, 36(20): 3250-3252+3256.
[9] Alsahli S, Al Anazi A, Al Hatlani MM, et al.Severe Crohn's Disease Manifestations in a Child with Cystathionine β-Synthase Deficiency[J]. ACG Case Rep J, 2018, 5(5): e93.
[10] Pan L, Yin Y, Chen J, et al.Homocysteine, vitamin B12, and folate levels in patients with multiple sclerosis in Chinese population: A case-control study and meta-analysis[J]. Mult Scler Relat Disord, 2019, 36: 101395.
[11] Li S, Qiu B, Lu H, et al.Hyperhomocysteinemia Accelerates Acute Kidney Injury to Chronic Kidney Disease Progression by Downregulating Heme Oxygenase-1 Expression[J]. Antioxid Redox Signal, 2019, 30(13): 1635-1650.
[12] Lai SH, Tsai YW, Chen YC, et al.Obesity, hyperhomocysteinaemia and risk of chronic kidney disease: a population-based study[J]. Fam Pract, 2018, 35(3): 259-265.
[13] Pushpakumar S, Kundu S, Sen U.Hydrogen Sulfide Protects Hyperhomocysteinemia-Induced Renal Damage by Modulation of Caveolin and eNOS Interaction[J]. Sci Rep, 2019, 9(1): 2223.
[14] Huang YJ, Yang XQ, Zhai WS, et al.Clinicopathological features and prognosis of membranoproliferative-like Henoch-Schonlein purpura nephritis in children[J]. World J Pediatr, 2015, 11(4): 338-345.
[15] Yang XQ, Huang YJ, Zhai WS, et al.Correlation between endocapillary proliferative and nephrotic-range proteinuria in children with Henoch-Schonlein purpura nephritis[J]. Pediatr Nephrol, 2019, 34(4): 663-670.
[16] Zhang Q, Conley SM, Li G, et al.Rac1 GTPase Inhibition Blocked Podocyte Injury and Glomerular Sclerosis during Hyperhomocysteinemia via Suppression of Nucleotide-Binding Oligomerization Domain-Like Receptor Containing Pyrin Domain 3 Inflammasome Activation[J]. Kidney Blood Press Res, 2019, 44(4): 513-532.
[17] 刘昆, 谢琳, 曹军, 等. 同型半胱氨酸致足细胞凋亡中FoxO1 DNA甲基化水平增高[J]. 中国组织工程研究, 2021, 25(2): 269-273.
[18] Lu XY, Liu BC, Cao YZ, et al.High glucose reduces expression of podocin in cultured human podocytes by stimulating TRPC6[J]. Am J Physiol Renal Physiol, 2019, 317(6): 1605-1611.
[19] Chen X, Liu W, Xiao J, et al.FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury[J]. FASEB J, 2020, 34(10): 13300-13316.
基金
张家口市科技攻关计划项目（1921042D）; 2022年度河北省医学科学研究课题计划（20220602）
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