重复给予脂肪间充质干细胞可增强恩格列净对糖尿病肾病大鼠肾功能保护作用。
Repeated administration of adipose-derived mesenchymal stem cells added on beneficial effects of empagliflozin on protecting renal function in diabetic kidney disease rat.
机构信息
Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
出版信息
Biomed J. 2024 Apr;47(2):100613. doi: 10.1016/j.bj.2023.100613. Epub 2023 Jun 22.
BACKGROUND
Diabetic kidney disease (DKD) is one of the most significant public health burdens worldwide. This study explored the renal protections of combined adipose-derived mesenchymal stem cells (ADMSCs) and empagliflozin (EMPA) in DKD rats.
METHODS
Adult-male-SD rats were equally allocated into group 1 (sham-operated-control), group 2 (DKD), group 3 (DKD + EMPA/20 mg/kg/day since day-14 after CKD-induction), group 4 [DKD + ADMSCs (6.0 × 10/intrarenal-arterial-injection/post-day-28, followed by 1.2 × 10/intravenous injection post-days 35 and 42 after CKD-induction, i.e., defined as repeated administration)] and group 5 (DKD + ADMSCs + EMPA) and kidney was harvested post-day-60 CKD-induction.
RESULTS
The result showed that the blood sugar and circulatory levels of BUN/creatinine and the ratio of urine protein/creatinine at day 60 were greatly increased in group 2 as compared the SC (i.e., group 1), significantly increased in groups 3 and 4 than in groups 5, but these parameters showed the similar manner in groups 3 and 4, except for blood sugar that was significantly lower in group 3 than in group 4 (all p < 0.0001). The protein levels of inflammation (NF-κB/FNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized protein/p22-phox)/apoptosis (cleaved-caspase-3/cleaved-PARP/mitochondrial-Bax)/fibrosis (TGF-β/Smad 3)/mitochondrial/DNA-damaged (p-DRP1/γ-H2AX) biomarkers revealed a similar manner of creatinine level among the groups (all p < 0.0001). Kidney injury score/fibrotic area/oxidative-stress score (8-OHdG) and cellular levels of kidney-damaged biomarkers (KIM-1/γ-H2AX) showed a unanimous manner. In contrast, the cellular expressions of podocyte components (ZO-1/synaptopodin) revealed an antithetical manner of creatinine among the groups (all p < 0.0001).
CONCLUSION
Combined ADMSCs-EMPA was superior to just one therapy for protecting kidney function and ultra-structural integrity in DKD rodents.
背景
糖尿病肾病（DKD）是全球最重要的公共健康负担之一。本研究探讨了脂肪间充质干细胞（ADMSCs）联合恩格列净（EMPA）在 DKD 大鼠中的肾脏保护作用。
方法
成年雄性 SD 大鼠随机分为 5 组：第 1 组（假手术对照）、第 2 组（DKD）、第 3 组（DKD+EMPA/20mg/kg/天，自 CKD 诱导后第 14 天开始）、第 4 组[DKD+ADMSCs（6.0×10/肾内动脉注射/CKD 诱导后第 28 天，随后在第 35 天和第 42 天再次静脉注射 1.2×10/次），即定义为重复给药]和第 5 组（DKD+ADMSCs+EMPA），并于 CKD 诱导后第 60 天取肾。
结果
结果显示，与 SC（即第 1 组）相比，第 2 组（DKD）在第 60 天的血糖和循环血尿素氮/肌酐水平以及尿蛋白/肌酐比值显著升高，第 3 组和第 4 组明显高于第 5 组，但除第 3 组的血糖显著低于第 4 组外（均 p<0.0001），这两组的这些参数表现出相似的模式。炎症（NF-κB/FNF-α/MMP-9）/氧化应激（NOX-1/NOX-2/氧化蛋白/p22-phox）/细胞凋亡（cleaved-caspase-3/cleaved-PARP/线粒体-Bax）/纤维化（TGF-β/Smad 3）/线粒体/DNA 损伤（p-DRP1/γ-H2AX）标志物的蛋白水平在各组间也呈现出相似的肌酐水平变化趋势（均 p<0.0001）。肾脏损伤评分/纤维化面积/氧化应激评分（8-OHdG）和细胞损伤标志物（KIM-1/γ-H2AX）水平也呈现一致的变化趋势。相比之下，足细胞成分（ZO-1/synaptopodin）的细胞表达在各组间呈现出相反的肌酐水平变化趋势（均 p<0.0001）。
结论
ADMSCs-EMPA 联合治疗在 DKD 啮齿动物中优于单一治疗，可更好地保护肾功能和超微结构完整性。
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