南方医科大学学报

南方医科大学学报 ›› 2023, Vol. 43 ›› Issue (12): 2053-2060.doi: 10.12122/j.issn.1673-4254.2023.12.09

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利格列汀通过激活AMPK/PGC-1α/TFAM通路改善糖尿病肾脏疾病线粒体生物合成

万 璐，钱宇池，倪文静，卢宇欣，李 巍，潘 艳，陈卫东   

  1. 蚌埠医科大学第一附属医院肾内科，临床检验诊断实验室，基础医学机能学综合实验室，安徽 蚌埠 233000
  • 出版日期:2023-12-20 发布日期:2023-12-29

Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1α/TFAM pathway

WAN Lu, QIAN Yuchi, NI Wenjing, LU Yuxin, LI Wei, PAN Yan, CHEN Weidong   

  1. Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China; Experimental Center of Clinical Laboratory Diagnostics, Functional Science laboratory, School of Basic Medicine, Bengbu Medical University, Bengbu 233000, China
  • Online:2023-12-20 Published:2023-12-29

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摘要： 目的 探究利格列汀是否能够通过激活磷酸腺苷活化蛋白激酶/过氧化物酶体增殖物激活受体γ共激活因子1α/线粒体转录因子A（AMPK/PGC-1α/TFAM）通路，改善糖尿病肾脏疾病（DKD）线粒体生物合成。方法 24只SD雄性大鼠，适应性喂养1周后，随机抽选6只大鼠为正常对照组（NC组）喂养普通饲料；剩下的予以4周高脂高糖饮食+45 mg/kg 1% STZ腹腔注射法造模，总计成功16只，将其随机分为DKD模型组（DKD组）、利格列汀干预组（DKD+Linagliptin组），每组8只，继续予以高脂高糖饲料喂养。DKD+Linagliptin组用5 g/L羧甲基纤维素钠配置2 mg/mL的利格列汀5 mg/（kg·d）给予大鼠灌胃12周，NC组、DKD组大鼠给予等量羧甲基纤维素钠灌胃。干预结束后将大鼠处死，留取腹主动脉血液和肾脏组织进行检测。检测血糖、肝功能及脂代谢情况；行 HE、PAS、Masson、天狼猩红染色及电镜观察肾脏组织损害情况；免疫组织化学法检测转化生长因子β1（TGF-β1）、纤连蛋白（FN）和胶原蛋白Ⅰ（COLⅠ）表达变化；检测组织细胞膜电位变化和ATP酶含量明确线粒体损伤情况；Western blot检测AMPK 、P-AMPK、PGC-1α、TFAM表达变化。结果 与DKD组相比，利格列汀治疗后，血糖水平（P<0.01）、蛋白尿（P<0.05）显著降低，肾脏病理、超微结构损伤明显减轻，TGF-β1、FN、COLⅠ的表达明显下降（P<0.05），线粒体膜电位增加且ATP酶含量上升（P<0.0001），线粒体生物合成相关蛋白 P-AMPK/AMPK、PGC-1α、TFAM表达增加（P<0.05）。结论 在DKD中，利格列汀具有降低尿白蛋白，善肾脏纤维化的作用。这种作用可能是通过激活AMPK/PGC-1α/TFAM通路，促进线粒体生物合成介导的。

关键词: 利格列汀；糖尿病肾脏疾病；线粒体生物合成；AMPK/PGC-1α/TFAM 信号通路

Abstract: Objective To investigate whether linagliptin improves diabetic kidney disease (DKD) by promoting mitochondrial biosynthesis via activating adenosine monophosphate activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α/mitochondrial transcription factor A (AMPK/PGC-1α/TFAM) pathway. Methods With 6 male SD rats feeding normal chow as the control group, 16 SD rat models of DKD induced by intraperitoneal injection of 45 mg/kg STZ and high-fat and high-glucose feeding for 4 weeks were randomized into DKD model group and linagliptin treatment group. The rats in the latter two groups were subjected to daily intragastric administration of vehicle or 5 mg/kg linagliptin (dissolved in 5 g/L sodium carboxymethylcellulose, final concentration of 2 mg/mL) for 12 weeks with further high-fat and high- glucose feeding. After the treatments, the rats were sacrificed and blood samples from the abdominal aorta and kidney tissues were collected for testing blood glucose, liver function and lipid metabolism; HE, PAS, Masson, Sirius red staining and electron microscopy were used to observe renal tissue damage. Renal expressions of transforming growth factor β1 (TGF-β1), fibronectin (FN) and collagen I (Col I) were detected by immunohistochemistry, and the changes in membrane potential (ΔψM) and ATP enzyme content were analyzed to assess mitochondrial damage; The expressions of AMPK/PGC-1α/TFAM pathway proteins were detected using Western blotting. Results Compared with DKD model rats, the rats receiving linagliptin treatment showed significantly decreased blood glucose level (P<0.01) and improved proteinuria (P<0.05) with obviously alleviated renal ultrastructural damage and fibrosis, increased ATPase content and ΔψM (P<0.0001), and enhanced renal expressions of P-AMPK/AMPK, PGC-1α and TFAM (P<0.05). Conclusions Linagliptin improves proteinuria and renal fibrosis in rat models of DKD possibly by activating the AMPK/PGC-1α/TFAM pathway to promote mitochondrial biosynthesis.

Key words: linagliptin; diabetic kidney disease; mitochondrial biogenesis; AMPK/PGC-1α/TFAM signaling pathway