Journal of Shandong University (Health Sciences) ›› 2020, Vol. 58 ›› Issue (3): 75-80.doi: 10.6040/j.issn.1671-7554.0.2019.1510

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Daglixamine inhibits renal fibrosis in rats with diabetic nephropathy via Klotho/TGF-β1 signaling pathway

DING Hualin1, LI Yangyang2, YU Fengyuan1, ZHAN Weiwei1, YU Suguo1   

  1. 1. Department of Endocrinology;
    2. Department of Pathology, Affiliated Hospital of Binzhou Medical College, Binzhou 256603, Shandong, China
  • Online:2020-03-10 Published:2022-09-27

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Abstract: Objective To investigate the effect of daglicaten on renal fibrosis in rats with diabetes-related nephropathy(DN)and to explore the possible mechanism. Methods A total of 20 male SD rats were randomly divided into the normal control group, model group, metformin group and daglipetide group, with 5 rats in each group. After models were established, the rats were divided into different groups for intervention. The renal function indexes were detected after 12 weeks, including blood urea nitrogen(BUN), serum creatinine(Scr)and 24-hour urine protein(24 h UP). The morphological changes were observed with HE staining. The expressions of Klotho protein and transforming growth factor β1(TGF-β1)in serum and kidney tissues were detected with ELISA and immunohistochemistry. Results The model group had significantly higher BUN, Scr, and 24 h UP than the normal control group(P<0.01); the metformin group had significantly lower BUN, Scr, and 24 h UP than the model group(P<0.05); the dagalegrin group had lower BUN, Scr, and 24 h UP than the metformin group(P<0.05). The model group had worse renal tubular injury than the normal group(9.4±0.55 vs 2.8±1.00, P<0.01); the metformin group had less renal tubular injury than the model group 山 东 大 学 学 报 (医 学 版)58卷3期 -丁华琳,等.达格列净通过Klotho/TGF-β1通路抑制糖尿病肾病大鼠肾纤维化的作用 \=-(7.0±0.90 vs 9.4±0.55, P<0.05); the daglicaten group had less renal tubular injury than the metformin group(5.6±1.0 vs 7.0±0.90, P<0.05). The model group had lower Klotho protein but higher TGF-β1 levels than the normal control group; the metformin group had higher Klotho protein but lower TGF-β1 levels than the model group; the daglicaten group had higher Klotho protein but lower TGF-β1 levels than the metformin group; all differences were statistically significant(P<0.05). Conclusion Daglipine inhibits TGF-β1-mediated fibrosis signaling by up-regulating Klotho protein expression and thus attenuates renal fibrosis in rats with diabetes-related nephropathy.

Key words: Daglipine, Klotho protein, Transforming growth factor β1, Diabetic nephropathy, Fibrosis signal transduction, SD rats

CLC Number: 

  • R587.2
[1] 朱辟疆. 肾脏纤维化与抗纤维化治疗研究[J]. 中国中西医结合肾病杂志, 2004, 5(2): 114-117.
[2] Li Y, Li L, Zeng O, et al. HS improves renal fibrosis in STZ-induced diabetic rats by ameliorating TGF-β1 expression [J]. Ren Fail, 2017, 39(1): 265-272.
[3] Cho NJ, Han DJ, Lee JH, et al. Soluble klotho as a marker of renal fibrosis and podocyte injuries in human kidneys [J]. PLoS One, 2018, 13(3): e0194617. doi:10.1371/journal.pone.0194617.
[4] Xue J, Wang L, Sun Z, et al. Basic research in diabetic nephropathy health care: a study of the renoprotective mechanism of metformin [J]. J Med Syst, 2019, 43(8): 266.
[5] Shen Y, Miao N, Xu J. Metformin prevents renal fibrosis in mice with unilateral ureteral obstruction and inhibits ang II-induced ECM production in renal fibroblasts [J]. Int J Mol Sci, 2016, 17(2): 146.
[6] Rajasekeran H, Lytvyn Y. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis [J]. Kidney Int, 2016, 89(3): 524-526.
[7] Elsherbiny NM, El-Sherbiny M. Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib [J]. Physiol Biochem, 2015, 71(4): 635-648.
[8] Goujon JM, Hauet T, Menet E, et al. Histological evaluation of proximal tubule cell injury in isolated perfused pig kidneys exposed to cold ischemia [J]. J Surg Res, 1999, 82(2): 228-233.
[9] Torsello B, Bianchi C, Meregalli C, et al. Correction: Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions [J]. J Cell Sci, 2019, 132(19): 2925-2936.
[10] Lu Q, Wang WW, Zhang MZ, et al. ROS induces epithelial-mesenchymal transition via the TGF-β1/PI3K/Akt/mTOR pathway in diabetic nephropathy [J]. Exp Ther Med, 2019, 17(1): 835-846.
[11] 洪郁之, 俞东容, 朱斌, 等. 雷公藤内酯醇对糖尿病肾内高压牵张系膜细胞模型细胞因子表达的抑制[J]. 中华糖尿病杂志, 2005, 13(6): 467-468.
[12] Tang F, Hao Y, Zhang X. Effect of echinacoside on kidney fibrosis by inhibition of TGF-β1/Smads signaling pathway in the db/db mice model of diabetic nephropathy [J]. Drug Des Devel Ther, 2017, 11(3): 2813-2826.
[13] Higgins SP,Tang Y, Higgins CE, et al. TGF-β1/p53 signaling in renal fibrogenesis [J]. Cell Signal, 2018, 43: 1-10. doi:10.1016/j.cellsig.2017.11.005.
[14] Lee HJ, Gonzalez O, Dick EJ, et al. Marmoset as a model to study kidney changes associated with aging [J]. J Gerontol A Biol Sci Med Sci, 2019, 74(3): 315-324.
[15] 缪静龙, 刘其锋. Klotho抑制肾间质纤维化的作用及机制[J]. 医学综述, 2019, 25(20): 3985-3990.
[16] Yin S, Zhang Q, Yang J, et al. TGFβ-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fibrosis [J]. Biochim Biophys Acta Mol Cell Res, 2017, 1864(7): 1207-1216.
[17] Huang JS, Chuang CT, Liu MH, et al. Klotho attenuates high glucose-induced fibronectin and cell hypertrophy via theERK1/2-p38 kinase signaling pathway in renal interstitial fibroblasts [J]. Mol Cell Endocrinol, 2014, 390(1/2): 45-53.
[18] Irifuku T, Doi S, Sasaki K, et al. Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression [J]. Kidney Int, 2016, 89(1): 147-157.
[19] Fu B, Yang J, Chen J, et al. Preventive effect of Shenkang injection against high glucose-induced senescence of renal tubular cells [J]. Front Med, 2019, 13(2): 267-276.
[20] Ding J, Tang Q, Luo B, et al. Klotho inhibits angiotensin II-induced cardiac hypertrophy, fibrosis, and dysfunction in mice through suppression of transforming growth factor-β1 signaling pathway [J]. European journal of pharmacology, 2019, 859: 172549. doi: 10.1016/j.ejphar.2019.172549.
[21] Vancura A, Bu P, Bhagwat M, et al. Metformin as an Anticancer Agent [J]. Trends Pharmacol Sci, 2018, 39(10): 867-878.
[22] 薛婧. 二甲双胍对糖尿病肾病的肾保护作用机制[D]. 南京: 南京医科大学, 2019.
[23] Yi H, Huang C, Shi Y, et al. Metformin attenuates folic-acid induced renal fibrosis in mice [J]. J Cell Physiol, 2018, 233(9): 7045-7054.
[24] Paik J. Dapagliflozin: A Review in Type 1 Diabetes [J]. Drugs, 2019, 79(17): 1877-1884.
[25] Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts [J]. Free Radic Biol Med, 2017, 104: 298-310. doi: 10.1016/j.freeradbiomed.2017.01.035.
[26] Amalia G, Enrico R, Cristian G, et al. Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes [J]. Diabetes Obes Metab, 2020, 22(3): 393-403.
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