Objective To explore whether tea polyphenols (TP) improve kidney podocyte injury via mTOR/PINK1 mitophagy signaling pathway in aged type 2 diabetes model rats (T2DM). Methods Forty rats were adaptively fed for 1 week, then randomly divided into the control group (Con, n = 10) and the aged T2DM model group (n = 30) according to the body weight. The rats in the T2DM model group were fed a high-glucose and high-fat diet, and treated with D-galactose intraperitoneally every day. Meanwhile, rats in the Con group were fed a normal diet, and treated with the equal volume of saline by intraperitoneal injection. After 4 weeks, the T2DM model rats were injected with STZ 25 mg/kg. The Con rats were injected with the same volume of citric acid buffer. Then, fasting blood glucose (FBG) was measured on the14th day. Successful T2DM model was developed when FBG was greater than or equal to 16.7 mmol/L. The T2DM rats were randomly divided into the aged T2DM group (model group), the TP 300 mg/kg group (TP group) and the rosiglitazone 3 mg/kg group (RSG group, n=10, respectively). Then, the rats were given intragastric intervention for 8 weeks. FBG was detected by the blood glucose meter, and the expression of P53 in the kidneys was detected by Western blot. Kidney image and mass were recorded, kidney index was calculated, and 24-hour urinary protein (UP) content was measured using CBB method. The microstructure of renal podocytes was observed by transmission electron microscope (TEM). Finally, the expressions of Nephrin, LC3, P62, HSP60, mTOR, p-mTOR, and PINK1 in kidney were detected by Western blot. Results Compared with the Con group, the level of FBG and the expression of P53 in the model group were increased (P<0.05). The kidney was obviously swollen and enlarged, and both renal index and 24-hour UP content were markedly increased (P<0.05). The basement membrane was extensively thickened, and the podocyte foot process was in fusion and disordered arrangement. The expressions of Nephrin, PINK1 and the ratio of LC3II/LC3I were reduced. Moreover, the expressions of P62, HSP60, and p-mTOR were increased (P<0.05). Compared with the Model group, the level of FBG and the expression of P53 in the TP group were down-regulated (P<0.05). The swelling of the kidney, the structures of the basement membrane and podocyte foot process were improved. Meanwhile, a large number of autophagosomes or autophagolysosomes were observed. Both renal index and 24-hour UP content were reduced (P<0.05). The expressions of Nephrin, PINK1 and the ratio of LC3II/LC3I were up-regulated, while the expressions of P62, HSP60, and p-mTOR were down-regulated (P<0.05). Compared with the Model group, no significant difference was observed in the ratio of LC3II/LC3I and the expression of PINK1 in the RSG group (P>0.05). Conclusion TP can improve renal podocyte damage in the aged T2DM rats, and its mechanism is related to increased mitophagy mediated by the mTOR/PINK1 signaling pathway.
Key words
tea polyphenols /
aged T2DM /
kidney /
podocyte /
mitophagy /
mTOR/PINK1
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References
[1] International Diabetes Federation. IDF Diabetes Atlas (tenth edition2021)[EB/OL].(2021–12–06)[2022–09–12].https://diabetesatlas.orgatlas/tenth-edition/.
[2] Wu X, Du J, Li L, et al. Bayesian age-period-cohort prediction of mortality of type 2 diabetic kidney disease in China: a modeling study[J]. Front Endocrinol (Lausanne), 2021, 12: 767263.
[3] 王雪, 史可香, 余灿清, 等. 中国10个地区成年人慢性肾脏病流行情况及其生活方式影响因素[J]. 中华流行病学杂志, 2023, 44: 386–392.
[4] Li W, Wang Q, Du M, et al. Effects of overexpressing FoxO1 on apoptosis in glomeruli of diabetic mice and in podocytes cultured in high glucose medium[J]. Biochem Biophys Res Commun, 2016, 478: 612–617.
[5] 李文洁,陈兵,杨拯, 等. 罗格列酮治疗糖尿病肾病的系统评价[J]. 中国医院药学杂志, 2011, 31: 78–81.
[6] Kariharan T, Nanayakkara G, Parameshwaran K, et al. Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression[J]. Neurobiol Aging, 2015, 36: 1451–1461.
[7] 寇婕, 石梦茜, 吕晨慧, 等. 茶多酚通过抑制线粒体凋亡改善糖尿病肾病大鼠肾功能的研究[J]. 营养学报, 2023, 45: 70–75.
[8] 中华医学会糖尿病分会微血管并发症学组. 糖尿病肾病防治专家共识[J]. 中华糖尿病杂志, 2014, 6: 792–801.
[9] 刘亚平, 季虹, 荣海钦, 等. 不同性别大鼠在2型糖尿病造模过程中的稳定性[J]. 中国实验动物学报, 2008(1): 52–55.
[10] Barrière DA, Noll C, Roussy G, et al. Combination of high-fat/high-fructose diet and low-dose streptozo-tocin to model long-term type-2 diabetes complications[J].Sci Rep, 2018, 8: 424.
[11] 洪晶, 张娅俐, 闫莎莎, 等. D-半乳糖诱导衰老小鼠模型研究进展[J]. 中国比较医学杂志, 2023, 33: 136–142.
[12] Rufini A, Tucci P, Celardo I, et al. Senescence and aging: the critical roles of p53[J].Oncogene, 2013, 32: 5129–5143.
[13] Kariyanna SS, Light RP, Agarwal R.A longitudinal study of kidney structure and function in adults[J]. Nephrol Dial Transplant,2010,25:1120–1126.
[14] Dong R, Zhang X, Liu Y, et al. Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease[J]. Phytomedicine,2023,112: 154700.
[15] Hu Y, Ye S, Xing Y, et al. Saxagliptin attenuates glomerular podocyte injury by increasing the expression of renal nephrin and podocin in type 2 diabetic rats[J]. Acta Diabetol,2020,57: 279–286.
[16] Guo R, Wang P, Zheng X, et al. Corrigendum: SGLT2 inhibitors suppress epithelial-mesenchymal transition in podocytes under diabetic conditions via downregula-ting the IGF1R/PI3K pathway[J].Front Pharmacol,2022,13: 1074294.
[17] Klionsky D J, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy[J].Autophagy,2016,12: 1–222.
[18] Zheng T, Wang HY, Chen Y, et al. Src activation aggravates podocyte injury in diabetic nephropathy via suppression of FUNDC1-mediated mitophagy[J].Front Pharmacol,2022,13: 897046.
[19] Li W, He P, Huang Y, et al. Selective autophagy of intracellular organelles: recent research advances[J]. Theranostics,2021,11: 222–256.
[20] Wen D, Tan RZ, Zhao CY, et al. Astragalus mongholicus Bunge and Panax notoginseng (Burkill) F.H. Chen Formula for renal injury in diabetic nephropathy-in vivo and in vitro evidence for autophagy regulation[J].Front Pharmacol,2020,11: 732.
[21] Tang H, Yang M, Liu Y, et al. Melatonin alleviates renal injury by activating mitophagy in diabetic nephron- pathy[J]. Front Endocrinol (Lausanne), 2022, 13: 889729.
