背景:肾脏疾病对人类健康和生活质量具有重大负面影响。肾缺血/再灌注(I/R)损伤被认为是导致肾功能障碍和组织损伤的主要原因之一。氧化应激和炎症是细胞凋亡的原因,在肾I/R损伤中起关键作用。最近的研究表明,达格列净-一种用于治疗2型糖尿病的药物-可能通过减轻氧化应激和炎症对肾脏的I/R损伤发挥保护作用。我们的研究评估了达格列净在肾脏I/R损伤中的保护作用。
方法:将32只雄性Sprague-Dawley大鼠分为四组:1)不进行任何操作的对照组;2)手术但无I/R损伤的假手术对照组;3)30分钟I/R损伤的实验组;4)30分钟IR损伤和达格列净治疗的治疗组。第四治疗组接受通过口服管饲法每天一次递送的1mg/kg达格列净。通过测量中性粒细胞明胶酶相关脂质运载蛋白(NGAL)来评估所有大鼠,肌酐激酶(CR),血尿素氮(BUN),肾损伤分子-1(KIM-1),肌红蛋白(MYO),肌酐激酶(CK),乳酸脱氢酶(LDH)LD,GSH,超氧化物歧化酶(SOD),MDA,白细胞介素-6(IL-6),和肿瘤坏死因子-a(TNF-a和谷胱甘肽过氧化物酶(GSH-Px)水平。TUNEL和流式细胞术测定评估细胞凋亡。
结果:总体而言,暴露于I/R损伤30分钟后,NGAL水平显着升高,CR,BUN,CK,LDH,KIM-1和MYO(均p<0.05)。I/R损伤后炎症细胞因子水平(IL-6和TNF-a)也升高(p>0.05)。同时,I/R损伤可降低SOD和GSH-Px水平(p>0.05)。相比之下,I/R损伤后服用达格列净可减少肾损伤,增强抗氧化能力,抑制炎症反应(所有p>0.05),从而改善肾功能,同时减少氧化应激状态和炎症反应。进一步的研究表明,达格列净通过激活磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-AKT)信号通路对肾组织发挥保护作用,抑制细胞凋亡,并通过骨形态发生蛋白4(BMP4)促进增殖和自噬。
结论:这些发现证明达格列净保护肾脏免受I/R损伤,表明其治疗潜力。
BACKGROUND: Renal diseases have a significant negative impact on human health and the quality of life. Renal ischemia/reperfusion (I/R) injury is considered as one of the leading causes of renal dysfunction and tissue damage. Oxidative stress and inflammation are responsible for cellular apoptosis playing critical roles in renal I/R injury. Recent studies suggested that dapagliflozin-a medication used to treat Type 2 Diabetes-may exert protective effects on I/R injury in kidneys by alleviating oxidative stress and inflammation. Our study evaluated the protective effects of dapagliflozinon in renal I/R injury.
METHODS: A group of 32 male Sprague-Dawley rats were divided into four groups: 1) control group without any manipulation; 2) sham-operated control group with surgery but without I/R injury; 3) experimental group with 30-min I/R injury; and 4) therapeutic group with 30-min IR injury and dapagliflozin therapy. The fourth therapeutic group received 1 mg/kg dapagliflozin delivered once daily by oral gavage. All rats were evaluated by measurements of neutrophil gelatinase-associated lipocalin (NGAL), creatinine kinase (CR), blood urea nitrogen (BUN), kidney injury molecule-1 (KIM-1), myoglobin (MYO), creatinine kinase (CK), lactate dehydrogenase (LDH) LD, GSH, superoxide dismutase (SOD), MDA, interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a and glutathione peroxidase (GSH-Px) levels. TUNEL and flow cytometry assays evaluated apoptosis.
RESULTS: Overall, the 30-min exposure to I/R injury significantly elevated levels of NGAL, CR, BUN, CK, LDH, KIM-1, and MYO (all p < 0.05). Inflammatory cytokine levels (IL-6 and TNF-a) were also increased after I/R injury (p > 0.05). At the same time, I/R injury decreased levels of SOD and GSH-Px (p > 0.05). In contrast, administration of dapagliflozin following I/R injury reduced renal damage, enhanced antioxidant capacity, and suppressed inflammatory responses (all p > 0.05), thus improving renal function, while reducing oxidative stress status and inflammatory responses. Further investigations revealed that dapagliflozin exerted its protective effects on renal tissues by activating the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, inhibiting cellular apoptosis, and promoting proliferation and autophagy through bone morphogenetic protein 4 (BMP4).
CONCLUSIONS: These findings documented that dapagliflozin protected kidneys from I/R injury suggesting its therapeutic potential.