[1]刘晨岩,刘致中.hUSCs通过调控SPHK1/S1P通路对糖尿病大鼠肾缺血再灌注损伤的改善作用[J].陕西医学杂志,2026,(8):1019-1025.[doi:DOI:10.3969/j.issn.1000-7377.2026.08.002]
　LIU Chenyan,LIU Zhizhong.Improvement effect of human urine-derived stem cells on renal ischemia-reperfusion injury in diabetic rats by regulating SPHK1/S1P pathway[J].,2026,(8):1019-1025.[doi:DOI:10.3969/j.issn.1000-7377.2026.08.002]
点击复制

hUSCs通过调控SPHK1/S1P通路对糖尿病大鼠肾缺血再灌注损伤的改善作用

《陕西医学杂志》[ISSN:1000-7377/CN:61-1281/TN]

卷:
期数:
2026年8期
页码:
1019-1025
栏目:
基础研究
出版日期:
2026-08-05

文章信息/Info

Title:
Improvement effect of human urine-derived stem cells on renal ischemia-reperfusion injury in diabetic rats by regulating SPHK1/S1P pathway
作者:
刘晨岩; 刘致中
（内蒙古医科大学第三临床医学院，内蒙古 包头 014010）
Author(s):
LIU Chenyan; LIU Zhizhong
(The Third Clinical Medical College of Inner Mongolia Medical University,Baotou 014010,China)
关键词:
糖尿病; 肾缺血再灌注损伤; 人尿源性干细胞; 鞘氨醇激酶1/鞘氨醇-1-磷酸通路; 炎症反应; 大鼠
Keywords:
Diabetes mellitus; Renal ischemia-reperfusion injury; Human urine-derived stem cells; Sphingosine kinase 1/sphingosine-1-phosphate pathway; Inflammatory response; Rats
分类号:
R -33
DOI:
DOI:10.3969/j.issn.1000-7377.2026.08.002
文献标志码:
A
摘要:
目的：探讨人尿源性干细胞（hUSCs）是否通过调控鞘氨醇激酶1（SPHK1）/鞘氨醇-1-磷酸（S1P）通路改善糖尿病大鼠肾缺血再灌注损伤（RIRI）。方法：选取雄性SD大鼠60只，随机分为对照组（Con组）、假手术组（Sham组）、RIRI组、SPHK1抑制剂PF543组（PF543组）、hUSCs组、hUSCs+SPHK1激活剂佛波酯（PMA）组（hUSCs+PMA组），每组10只。除Con组外，其余组大鼠建立糖尿病大鼠模型。除Con组和Sham组外，其余组大鼠均建立RIRI模型，各组大鼠均于造模前30 min干预。PF543组大鼠尾静脉注射7 mg/kg PF543；hUSCs组大鼠尾静脉注射50 μl 含5×105个hUSCs的PBS；hUSCs+PMA组大鼠尾静脉注射50 μl 含5×105个hUSCs的PBS和200 μg/kg PMA；Con组、Sham组和RIRI组尾静脉注射等量0.9%氯化钠溶液。检测大鼠血清肌酐（SCr）、尿素氮（BUN）、胱抑素C（Cys C）、白细胞介素-1β（IL-1β）、IL-6、肿瘤坏死因子-α（TNF-α）水平及尿液肾损伤分子-1（KIM-1）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）水平；HE染色观察肾脏组织病理学变化；TUNEL染色检测肾脏组织细胞凋亡情况；Western blot检测肾脏组织活化的半胱氨酸天冬氨酸蛋白酶-3（cleaved Caspase-3）、SPHK1和S1P蛋白表达。结果：与Con组比较，Sham组大鼠肾脏组织有少量炎症细胞浸润，血清IL-1β、TNF-α、IL-6水平升高（均P<0.05）。与Sham组比较，RIRI组大鼠肾脏组织呈现典型的急性肾小管损伤特征，血清BUN、SCr、Cys C、IL-1β、TNF-α、IL-6水平、尿液KIM-1和NGAL水平、肾脏组织病理评分、细胞凋亡率、cleaved Caspase-3、SPHK1和S1P蛋白表达水平升高（均P<0.05）。与RIRI组比较，PF543组和hUSCs组大鼠肾脏病理学变化有明显改善，血清BUN、SCr、Cys C、IL-1β、TNF-α、IL-6水平、尿液KIM-1和NGAL水平、肾脏组织病理评分、细胞凋亡率、cleaved Caspase-3、SPHK1和S1P蛋白表达水平降低（均P<0.05）。PF543组和hUSCs组各指标比较差异无统计学意义（均P>0.05）。PMA可降低hUSCs对糖尿病大鼠RIRI的改善作用。结论：hUSCs可降低糖尿病大鼠RIRI炎症反应和细胞凋亡，减轻肾脏组织损伤，改善肾脏功能，其作用机制可能与抑制SPHK1/S1P通路有关。
Abstract:
Objective:To explore whether human urine-derived stem cells (hUSCs) can improve renal ischemia-reperfusion injury (RIRI) in diabetic rats by regulating sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway.Methods:Sixty male SD rats were selected and randomly divided into control group (Con group),sham operation group (Sham group),RIRI group,SPHK1 inhibitor PF543 group (PF543 group),hUSCs group,hUSCs+SPHK1 activator PMA group (hUSCs+PMA group),with 10 rats in each group.Diabetic rat models were established in rats of all groups except the Con group.RIRI models were established in rats of all groups except the Con group and Sham group.Interventions were performed on rats of each group 30 minutes before model establishment.Rats in PF543 group were injected with 7 mg/kg PF543 via tail vein;rats in hUSCs group were injected with 50 μl PBS containing 5×105 hUSCs via tail vein;rats in hUSCs+PMA group were injected with 50 μl PBS containing 5×105 hUSCs and 200 μg/kg PMA via tail vein;rats in Con group,Sham group and RIRI group were injected with equal volume of 0.9% sodium chloride solution via tail vein.The serum levels of serum creatinine (SCr),blood urea nitrogen (BUN),cystatin C (Cys C),interleukin-1β (IL-1β),IL-6 and tumor necrosis factor-α (TNF-α),as well as urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were detected.HE staining was used to observe renal histopathological changes.TUNEL staining was adopted to detect renal tissue cell apoptosis.Western blot was utilized to detect protein expressions of cleaved Caspase-3,SPHK1 and S1P in renal tissues.Results:Compared with the Con group,a small amount of inflammatory cell infiltration was observed in renal tissues of rats in the Sham group,and serum levels of IL-1β,TNF-α and IL-6 were increased (all P<0.05).Compared with the Sham group,rats in the RIRI group presented typical characteristics of acute renal tubular injury in renal tissues;serum levels of BUN,SCr,Cys C,IL-1β,TNF-α,IL-6,urinary levels of KIM-1 and NGAL,renal histopathological score,cell apoptosis rate,and protein expression levels of cleaved Caspase-3,SPHK1 and S1P were all increased (all P<0.05).Compared with the RIRI group,renal pathological changes of rats in PF543 group and hUSCs group were significantly improved;serum levels of BUN,SCr,Cys C,IL-1β,TNF-α,IL-6,urinary levels of KIM-1 and NGAL,renal histopathological score,cell apoptosis rate,and protein expression levels of cleaved Caspase-3,SPHK1 and S1P were all decreased (all P<0.05).There was no statistically significant difference in each index between PF543 group and hUSCs group (all P>0.05).PMA could reduce the improvement effect of hUSCs on RIRI in diabetic rats.Conclusion:hUSCs can reduce inflammatory response and cell apoptosis,alleviate renal tissue injury and improve renal function in diabetic rats with RIRI,and its mechanism of action may be related to the inhibition of SPHK1/S1P pathway.

参考文献/References:

[1]CHEN X,YU Y,XIAO C,et al.Huangkui capsules for diabetic nephropathy:Comprehensive review of efficacy and molecular mechanisms[J].Phytomedicine,2025,147(2):157207-157218.
[2]杨明正,阚林,刘娟,等.TANK结合激酶1、白介素-6、肿瘤坏死因子-α在2型糖尿病肾病患者中表达变化及临床意义[J].陕西医学杂志,2026,55(4):550-554,560.
[3]QIN X,LIU J,ZHAO X,et al.Platycodin D attenuates diabetic renal ischemia/reperfusion injury by enhancing mitophagy and suppressing MAPK/NF-κB signaling activation[J].Biochim Biophys Acta Mol Basis Dis,2025,1871(8):168026-168037.
[4]PENG P,ZOU J,ZHONG B,et al.Protective effects and mechanisms of flavonoids in renal ischemia-reperfusion injury[J].Pharmacology,2023,108(1):27-36.
[5]KHANG A R,KIM D H,KIM M J,et al.Reducing oxidative stress and inflammation by pyruvate dehydrogenase kinase 4 inhibition is important in prevention of renal ischemia-reperfusion injury in diabetic mice[J].Diabetes Metab J,2024,48(3):405-417.
[6]杨博鑫,杨硕,崔丽艳.尿源性干细胞对急性肾损伤的保护作用及机制研究进展[J].国际检验医学杂志,2021,42(23):2919-2922.
[7]HUO G,GENG J,LIU X,et al.Isolated monoclonal human urine-derived stem cells showed differential therapeutic effects on renal ischemia-reperfusion injury in mice[J].Biomedicines,2025,13(12):2911-2923.
[8]LI F,ZHAO B,ZHANG L,et al.Therapeutic potential of urine-derived stem cells in renal regeneration following acute kidney injury:A comparative analysis with mesenchymal stem cells[J].World J Stem Cells,2024,16(5):525-537.
[9]YANG X,WANG Q,NIE H,et al.Hypoxia-inducible factor 2α overexpression in podocytes ameliorates lipid metabolism disorders in diabetic kidney disease by inhibiting S1P[J].Ren Fail,2025,47(1):2568972.
[10]汤舒,邹吉利,安靖,等.龙葵提取物基于SphK1/S1P信号通路对慢性肾炎大鼠血清炎性因子及肾功能的影响[J].中国老年学杂志,2025,45(17):4266-4270.
[11]YAKYMENKO O,SUCHOK S,LUKIIANETS O,et al.Macroscopic and histopathological features of acute peritoneal infection in diabetic and euglycemic Wistar rats[J].Pediatr Endocrinol Diabetes Metab,2022,28(1):30-34.
[12]FENG M,AN Y,QIN Q,et al.Sphk1/S1P pathway promotes blood-brain barrier breakdown after intracerebral hemorrhage through inducing Nlrp3-mediated endothelial cell pyroptosis[J].Cell Death Dis,2024,15(12):926.
[13]周中华,王彤彤,谭伟,等.姜黄素调节SphK1/S1P信号通路对糖尿病合并冠心病大鼠心脏功能的影响[J].南开大学学报(自然科学版),2024,57(5):11-17.
[14]黄亚医,周芳,沈成,等.右美托嘧啶对糖尿病大鼠肾缺血再灌注损伤的保护作用[J].中国临床药理学杂志,2022,8(15):1761-1765.
[15]高建辉,薛莹,张佳齐,等.瑞马唑仑对大鼠急性肾缺血再灌注损伤的影响及机制[J].山西医科大学学报,2024,55(5):621-626.
[16]ZHANG L,WANG Z,WU Y,et al.RasGRP4 aggravates ischemia-reperfusion injury in diabetic kidneys by mediating communication between macrophages and T cells[J].JCI Insight,2024,10(2):e187653.
[17]崔田宁,刘涛,肖向阳,等.尿源性干细胞及细胞外囊泡在组织损伤修复中的作用[J].中国组织工程研究,2021,25(31):5046-5052.
[18]王蕊,赵伟,樊春阳,等.人尿源干细胞微囊泡调控FAS/FADD信号通路改善糖尿病肾病线粒体功能障碍[J].解剖科学进展,2026,3(1):21-26.
[19]王利元,李晶,刘芳,等.益气养阴方配合他克莫司治疗肾病综合征患者肾功能、外周血Th17/Treg免疫平衡、NF-κB信号转导通路的影响[J].陕西中医,2026,47(3):355-359.
[20]JANA S,MITRA P,DUTTA A,et al.Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model[J].Curr Res Toxicol,2023,5:100135.
[21]REN L,ZHAO Y,JI X,et al.The therapeutic effect of Picroside Ⅱ in renal ischemia-reperfusion induced acute kidney injury:An experimental study[J].Eur J Pharmacol,2024,967:176391.
[22]WANG K,XU C,WANG H,et al.Puerarin protects against renal ischemia-reperfusion injury by restoring mitochondrial function and modulating the PI3K/AKT/NF-κB pathway and suppressing inflammatory responses[J].Cell Signal,2026,139:112350.
[23]YOUNIS N S.Myrrh essential oil mitigates renal ischemia/reperfusion-induced injury[J].Curr Issues Mol Biol,2023,45(2):1183-1196.
[24]ZHANG B,CHEN Z Y,JIANG Z,et al.Nephroprotective effects of cardamonin on renal ischemia reperfusion injury/UUO-induced renal fibrosis[J].J Agric Food Chem,2023,71(36):13284-13303.
[25]UEDA N.A rheostat of ceramide and sphingosine-1-phosphate as a determinant of oxidative stress-mediated kidney injury[J].Int J Mol Sci,2022,23(7):4010-4021.
[26]邹鑫,于冰,徐龙辉,等.吴茱萸碱调节SphK1/S1P信号通路对慢性肾衰竭大鼠肾纤维化的影响[J].广州中医药大学学报,2024,41(6):1560-1566.
[27]LAN J P,XUE Y F,PU J Y,et al.Plantaginis semen ameliorates diabetic kidney disease via targeting the sphingosine kinase 1/sphingosine-1-phosphate pathway[J].J Ethnopharmacol,2024,331:118221.

相似文献/References:

[1]段继源,王光哲,曹艳,等.胰岛素强化治疗对急性冠脉综合征合并糖尿病患者PCI术后血小板功能的影响[J].陕西医学杂志,2016,(10):1411.
[2]叶睿,任力杰.2型糖尿病患者下肢动脉病变发生率及危险因素分析[J].陕西医学杂志,2016,(10):1426.
[3]庄晖,李利波,梁梅珍,等.妊娠期糖尿病孕妇胎儿脐动脉频谱血流收缩期最大血流速度与舒张期血流速度比值对胎儿宫内窘迫的预测价值[J].陕西医学杂志,2017,(06):715.
[4]严玲玲,苏建彬 △,王雪琴.胰岛α细胞功能与2型糖尿病肾脏病变相关性研究[J].陕西医学杂志,2018,(12):1576.
[5]齐婷,左红,黎国红,等.不同剂量阿托伐他汀钙片联合阿司匹林肠溶片对糖尿病患者动脉粥样硬化斑块稳定性影响的对比分析*[J].陕西医学杂志,2019,(1):92.
　QI Ting,ZUO Hong,LI Guohong,et al.Comparative analysis of the effects of different doses of atorvastatin tablets combined withaspirin entericcoated tablets on the stability of diabetic atherosclerotic plaque[J].,2019,(8):92.
[6]汤克虎,高峻峰,任尽平.药物涂层球囊在糖尿病患者冠状动脉小血管病变治疗中的应用研究*[J].陕西医学杂志,2019,(4):432.
[7]周 祎,张 宁,刘晓荣,等.结核感染T淋巴细胞实验和Xpert MTB/RIF检测在糖尿病并发菌阴性肺结核患者诊断中的价值*[J].陕西医学杂志,2019,(7):885.
　ZHOU Yi,ZHANG Ning,LIU Xiaorong,et al.Diagnostic efficiency of T-SPOT.TB and Gen-Xpert MTB/RIF in detecting smear-negative pulmonary tuberculosis combined with diabetes mellitus.[J].,2019,(8):885.
[8]陈辅萍.慢性阻塞性肺疾病并发感染性肺炎危险因素分析[J].陕西医学杂志,2020,49(1):102.
[9]王 晶,刘易婷,刘 哲.替米沙坦联合瑞舒伐他汀治疗糖尿病合并冠心病对患者外周胰岛素抵抗、糖化血红蛋白、脂蛋白和心肌缺血的影响[J].陕西医学杂志,2022,51(5):595.[doi:DOI:10.3969/j.issn.1000-7377.2022.05.019]
　WANG Jing,LIU Yiting,LIU Zhe.Effects of telmisartan combined with rosuvastatin on peripheral insulin resistance,glycosylated hemoglobin,lipoproteins and myocardial ischemia in diabetic patients with coronary heart disease[J].,2022,51(8):595.[doi:DOI:10.3969/j.issn.1000-7377.2022.05.019]
[10]韦文合.达格列净联合唑来膦酸治疗老年糖尿病合并骨质疏松症疗效及对患者骨代谢、骨密度水平的影响[J].陕西医学杂志,2023,52(11):1574.[doi:DOI:10.3969/j.issn.1000-7377.2023.11.027]
　WEI Wenhe.Efficacy of dapagliflozin combined with zoledronic acid in treatment of elderly diabetic patients with osteoporosis and its effect on bone metabolism and bone mineral density[J].,2023,52(8):1574.[doi:DOI:10.3969/j.issn.1000-7377.2023.11.027]

备注/Memo

备注/Memo:
内蒙古自治区自然科学基金资助项目(2022MS08052)；内蒙古自治区包头市卫生健康科技计划项目(2024wsjkkj48)
更新日期/Last Update: 2026-08-13