目的: 探讨人脐带间充质干细胞对糖尿病肾病大鼠肾组织损伤及尿调蛋白的表达的影响。方法: 建立糖尿病肾病模型,分为正常对照组(NC组)、糖尿病肾病(diabetic kidney disease, DKD)组(DKD组),以及人脐带间充质干细胞(human umbilical cord mesenchymal stem cells, HU-MSCs)治疗糖尿病肾病组(HU-MSCs+DKD组)。检测HU-MSCs治疗糖尿病肾病大鼠前后肾组织及尿液尿调蛋白(uromodulin, UMOD)水平和相关因子的表达。结果: DKD组大鼠肾损伤早期,尿液和肾间质中UMOD水平升高(P＜0.001),远端小管标记蛋白SLC12a3表达下降。与对照组相比,HU-MSCs治疗后能显著降低DKD大鼠血清尿素氮(P＜0.01)、24 h尿蛋白水平(P＜0.05)及尿白蛋白/肌酐比(均P＜0.05)。HU-MSCs治疗后肾小球体积减小,系膜细胞和基底膜增厚减轻,肾小管损伤减轻,尿液和肾间质UMOD表达下降,SLC12a3的水平升高。结论: 在糖尿病肾病早期,HU-MSCs可以减轻肾组织损伤,其减轻肾小管损伤与肾脏组织尿调蛋白达的降低有关。
Objective: To investigate the effects of human umbilical cord mesenchymal stem cells on renal tissue injury and expression of uromodulin in rats with diabetic nephropathy. Methods: The diabetic nephropathy model was established and divided into normal control group (NC group), diabetic kidney disease (DKD) group (DKD group), and human umbilical cord mesenchymal stem cells (HU-MSCs) treatment of diabetic nephropathy group (HU-MSCs+DKD group). The expression of uromodulin (UMOD) and related factors in renal tissue and urine of diabetic nephropathy rats before and after HU-MSCs treatment was detected. Results: In the early stage of renal injury in DKD group, the level of UMOD in urine and renal interstitium increased (P＜0.001), and the expression of distal tubule marker protein SLC12a3 decreased. Compared with the control group, HU-MSCs treatment significantly reduced serum urea nitrogen (P＜0.01), 24-hour urinary protein (P＜0.05), and urinary albumin / creatinine ratio (P＜0.05) in DKD rats. After HU-MSCs treatment, glomerular volume decreased, mesangial cells and basement membrane thickening decreased, renal tubular injury decreased, urine and renal interstitial UMOD expression decreased, and SLC12a3 level increased. Conclusion: In the early stage of diabetic nephropathy, HU-MSCs can reduce renal tissue injury, and its reduction of renal tubular injury is related to the decrease of uromodulin in renal tissue.
[1] Lin E, Erickson KF. Payer mix among patients receiving dialysis[J]. JAMA, 2020, 324(9): 900-901.
[2] Matoba K, Takeda Y, Nagai Y, et al. Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease[J]. Int J Mol Sci, 2019, 20(14):3393.
[3] Kipp A, Olinger E. What does uromodulin do?[J]. Clin J Am Soc Nephrol, 2020, 16(1): 150-153.
[4] Micanovic R, Khan S, Janosevic D, et al. Tamm-Horsfall Protein RegulatesMononuclear Phagocytes in the Kidney [J]. J Am Soc Nephrol, 2018, 29(3): 841-856.
[5] 修贤杰, 张萍, 郑小鹏, 等. 注射STZ方式对制备糖尿病肾病模型的影响研究[J]. 广东化工, 2020, 47(8): 59-60.
[6] Scheurlen KM, Billeter AT, Kopf S, et al. Serum uromodulin and rouxeny gastric bypass: improvement of a marker reflecting nephron mass[J]. Surg Obes Relat Dis, 2019, 15(8): 1319-1325.
[7] Then C, Then HL, Lechner A, et al. Serum uromodulin and risk for cardiovascular morbidity and mortality in the community-based KORA F4 study[J]. Atherosclerosis, 2020, 297: 1-7.
[8] Micanovic R, Lafavers K, Garimella PS, et al. Uromodulin (tamm-horsfall protein): guardian of urinary and systemic homeostasis[J]. Nephrol Dial Transplant, 2020, 35(1): 33-43.
[9] Bullen AL, Katz R, Lee AK, et al. The sprint trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury[J]. Kidney Int, 2019, 96(2): 470-479.
[10] Wuttke M, Li Y, Li M et al. A catalog of genetic loci asso-ciated with kidney function from analyses of a million individuals[J]. Nat Genet 2019, 51: 957-972.
[11] Schaeffer C, Devuyst O, Rampoldi L, et al. Uromodulin: Roles in health and disease[J]. Annu Rev Physiol. 2021, 83: 477-501.
[12] Ponte B, Sadler MC, Olinger E, et al. Mendelian randomization to assess causality between uromodulin, blood pressure and chronic kidney disease[J]. Kidney Int, 2021, 100(6): 1282-1291.
[13] Pfleiderer S, Zimmerhackl LB, Kinne R, et al. Renal proximal and distal tubular function is attenuated in diabetes mellitus type 1 as determined by the renal excretion of alpha 1-microglobulin and Tamm-Horsfall protein[J]. Clin Investig, 1993, 71(12): 972-977.
[14] Zimmerhackl LB, Pfleiderer S, Kinne R, et al. Tamm-Horsfall-Protein excretion as a marker of ascending limb transport indicates early renal tubular damage in diabetes mellitus type I[J]. Diabet Complications, 1991, 5(2-3): 112-114.
[15] Chakraborty J, Below AA, Solaiman D. Tamm-Horsfall protein in patients with kidney damage and diabetes[J]. Urol Res, 2004, 32(2): 79-83.
[16] 高欢. 脐带间充质干细胞对高糖环境下肾小管上皮细胞自噬的作用及相关机制研究[D].长春: 吉林大学, 2024.
[17] Immler R, Lange-Sperandio B, Steffen T, et al. Extratubular polymerized uromodulin induces leukocyte recruitment and inflammation in vivo[J]. Front Immunol, 2020, 11: 588245.
