Gastrodin inhibits high glucose‑induced inflammation, oxidative stress and apoptosis in podocytes by activating the AMPK/Nrf2 signaling pathway

Huang,Luyan; Shao,Minghai; Zhu,Yan

doi:10.3892/etm.2021.11091

Gastrodin inhibits high glucose‑induced inflammation, oxidative stress and apoptosis in podocytes by activating the AMPK/Nrf2 signaling pathway

Authors:
- Luyan Huang
- Minghai Shao
- Yan Zhu
View Affiliations

Affiliations: Department of Traditional Chinese Medicine, Zhongshan Hospital (Minhang Branch), Fudan University, Shanghai 201199, P.R. China, Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, P.R. China, Department of Traditional Chinese Medicine, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, P.R. China
Published online on: December 23, 2021 https://doi.org/10.3892/etm.2021.11091
Article Number: 168
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diabetic nephropathy (DN) is a serious and common complication of type 1 and 2 diabetes. Gastrodin has been reported to suppress high glucose (HG)‑induced inflammation and oxidative stress in vivo and in vitro. However, the effect of gastrodin on DN has not been fully elucidated. The present study aimed to investigate the underlying mechanism involved in the effect of gastrodin on podocyte injury caused by DN. Cell viability was evaluated using Cell Counting Kit‑8 assay and secretion levels of TNF‑α, IL‑1β and IL‑6 were measured using ELISA. The levels of malondialdehyde, activities of lactate dehydrogenase and superoxide dismutase were quantified using corresponding assay kits. Additionally, cell apoptosis was analyzed by TUNEL assay, whilst protein expressions related to inflammation, apoptosis and the 5'‑AMP‑activated protein kinase (AMPK)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling pathway were measured by western blot analysis. The results showed that gastrodin increased the viability of MPC5 cells following HG stimulation. Gastrodin also alleviated HG‑induced inflammation, oxidative stress and apoptosis in MPC5 cells. Furthermore, gastrodin promoted activation of the AMPK/Nrf2 pathway in MPC5 cells. Treatment with the AMPK inhibitor, compound C, reversed the inhibitory effects of gastrodin on inflammation, oxidative stress and cell apoptosis. To conclude, treatment of MPC5 cells with gastrodin can attenuate HG‑induced inflammation, oxidative stress and cell apoptosis by activating the AMPK/Nrf2 signaling pathway. Results from the current study suggest that gastrodin can be used as an effective therapeutic agent against HG‑induced podocyte injury in DN.

View Figures

View References

1	Gnudi L, Coward RJM and Long DA: Diabetic nephropathy: Perspective on novel molecular mechanisms. Trends Endocrinol Metab. 27:820–830. 2016.PubMed/NCBI View Article : Google Scholar
2	Yamahara K, Yasuda M, Kume S, Koya D, Maegawa H and Uzu T: The role of autophagy in the pathogenesis of diabetic nephropathy. J Diabetes Res. 2013(193757)2013.PubMed/NCBI View Article : Google Scholar
3	Gheith O, Farouk N, Nampoory N, Halim MA and Al-Otaibi T: Diabetic kidney disease: World wide difference of prevalence and risk factors. J Nephropharmacol. 5:49–56. 2016.PubMed/NCBI
4	Feng Y, Weng H, Ling L, Zeng T, Zhang Y, Chen D and Li H: Modulating the gut microbiota and inflammation is involved in the effect of Bupleurum polysaccharides against diabetic nephropathy in mice. Int J Biol Macromol. 132:1001–1011. 2019.PubMed/NCBI View Article : Google Scholar
5	Morigi M, Perico L, Corna D, Locatelli M, Cassis P, Carminati CE, Bolognini S, Zoja C, Remuzzi G, Benigni A and Buelli S: C3a receptor blockade protects podocytes from injury in diabetic nephropathy. JCI Insight. 5(e131849)2020.PubMed/NCBI View Article : Google Scholar
6	Zhang P, Fang J, Zhang J, Ding S and Gan D: Curcumin inhibited podocyte cell apoptosis and accelerated cell autophagy in diabetic nephropathy via regulating Beclin1/UVRAG/Bcl2. Diabetes Metab Syndr Obes. 13:641–652. 2020.PubMed/NCBI View Article : Google Scholar
7	Kim YI, Kim CH, Choi CS, Chung YE, Lee MS, Lee SI, Park JY, Hong SK and Lee KU: Microalbuminuria is associated with the insulin resistance syndrome independent of hypertension and type 2 diabetes in the Korean population. Diabetes Res Clin Pract. 52:145–152. 2001.PubMed/NCBI View Article : Google Scholar
8	Al-Rubeaan K, Siddiqui K, Alghonaim M, Youssef AM and AlNaqeb D: The Saudi diabetic kidney disease study (Saudi-DKD): Clinical characteristics and biochemical parameters. Ann Saudi Med. 38:46–56. 2018.PubMed/NCBI View Article : Google Scholar
9	Lopes TG, de Souza ML, da Silva VD, Dos Santos M, da Silva WIC, Itaquy TP, Garbin HI and Veronese FV: Markers of renal fibrosis: How do they correlate with podocyte damage in glomerular diseases? PLoS One. 14(e0217585)2019.PubMed/NCBI View Article : Google Scholar
10	Chen Y, Lin L, Tao X, Song Y, Cui J and Wan J: The role of podocyte damage in the etiology of ischemia-reperfusion acute kidney injury and post-injury fibrosis. BMC Nephrol. 20(106)2019.PubMed/NCBI View Article : Google Scholar
11	Ilatovskaya DV, Blass G, Palygin O, Levchenko V, Pavlov TS, Grzybowski MN, Winsor K, Shuyskiy LS, Geurts AM, Cowley AW Jr, et al: A NOX4/TRPC6 pathway in podocyte calcium regulation and renal damage in diabetic kidney disease. J Am Soc Nephrol. 29:1917–1927. 2018.PubMed/NCBI View Article : Google Scholar
12	Khalilpourfarshbafi M, Hajiaghaalipour F, Selvarajan KK and Adam A: Mesenchymal stem cell-based therapies against podocyte damage in diabetic nephropathy. Tissue Eng Regen Med. 14:201–210. 2017.PubMed/NCBI View Article : Google Scholar
13	Chen Y, Liu Q, Shan Z, Zhao Y, Li M, Wang B, Zheng X and Feng W: The protective effect and mechanism of catalpol on high glucose-induced podocyte injury. BMC Complement Altern Med. 19(244)2019.PubMed/NCBI View Article : Google Scholar
14	Zhan X, Yan C, Chen Y, Wei X, Xiao J, Deng L, Yang Y, Qiu P and Chen Q: Celastrol antagonizes high glucose-evoked podocyte injury, inflammation and insulin resistance by restoring the HO-1-mediated autophagy pathway. Mol Immunol. 104:61–68. 2018.PubMed/NCBI View Article : Google Scholar
15	Yu Q, Zhang M, Qian L, Wen D and Wu G: Luteolin attenuates high glucose-induced podocyte injury via suppressing NLRP3 inflammasome pathway. Life Sci. 225:1–7. 2019.PubMed/NCBI View Article : Google Scholar
16	Zhong Y, Lee K, Deng Y, Ma Y, Chen Y, Li X, Wei C, Yang S, Wang T, Wong NJ, et al: Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes. Nat Commun. 10(4523)2019.PubMed/NCBI View Article : Google Scholar
17	Xu CB, Guo QL, Wang YN, Lin S, Zhu CG and Shi JG: Gastrodin derivatives from gastrodia elata. Nat Prod Bioprospect. 9:393–404. 2019.PubMed/NCBI View Article : Google Scholar
18	Liu Y, Gao J, Peng M, Meng H, Ma H, Cai P, Xu Y, Zhao Q and Si G: A review on central nervous system effects of gastrodin. Front Pharmacol. 9(24)2018.PubMed/NCBI View Article : Google Scholar
19	Ye T, Meng X, Zhai Y, Xie W, Wang R, Sun G and Sun X: Gastrodin ameliorates cognitive dysfunction in diabetes rat model via the suppression of endoplasmic reticulum stress and NLRP3 inflammasome activation. Front Pharmacol. 9(1346)2018.PubMed/NCBI View Article : Google Scholar
20	Zhang TH, Huang CM, Gao X, Wang JW, Hao LL and Ji Q: Gastrodin inhibits high glucose-induced human retinal endothelial cell apoptosis by regulating the SIRT1/TLR4/NF-κBp65 signaling pathway. Mol Med Rep. 17:7774–7780. 2018.PubMed/NCBI View Article : Google Scholar
21	Cheng Y, Qi Y, Liu S, Di R, Shi Q, Li J and Pei C: C1q/TNF-related protein 9 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells through the activation of AMPK/Nrf2 signaling pathway. Cell Transplant. 29(963689720962052)2020.PubMed/NCBI View Article : Google Scholar
22	Xu W, Zhao T and Xiao H: The implication of oxidative stress and AMPK-Nrf2 antioxidative signaling in pneumonia pathogenesis. Front Endocrinol (Lausanne). 11(400)2020.PubMed/NCBI View Article : Google Scholar
23	Zhou F, Wang M, Ju J, Wang Y, Liu Z, Zhao X, Yan Y, Yan S, Luo X and Fang Y: Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation. Am J Transl Res. 11:199–209. 2019.PubMed/NCBI
24	Qu LL, Yu B, Li Z, Jiang WX, Jiang JD and Kong WJ: Gastrodin ameliorates oxidative stress and proinflammatory response in nonalcoholic fatty liver disease through the AMPK/Nrf2 pathway. Phytother Res. 30:402–411. 2016.PubMed/NCBI View Article : Google Scholar
25	Ma T, Zheng Z, Guo H, Lian X, Rane MJ, Cai L, Kim KS, Kim KT, Zhang Z and Bi L: 4-O-methylhonokiol ameliorates type 2 diabetes-induced nephropathy in mice likely by activation of AMPK-mediated fatty acid oxidation and Nrf2-mediated anti-oxidative stress. Toxicol Appl Pharmacol. 370:93–105. 2019.PubMed/NCBI View Article : Google Scholar
26	Wang RM, Wang ZB, Wang Y, Liu WY, Li Y, Tong LC, Zhang S, Su DF, Cao YB, Li L and Zhang LC: Swiprosin-1 promotes mitochondria-dependent apoptosis of glomerular podocytes via P38 MAPK pathway in early-stage diabetic nephropathy. Cell Physiol Biochem. 45:899–916. 2018.PubMed/NCBI View Article : Google Scholar
27	Han X, Li Q, Wang C and Li Y: MicroRNA-204-3p attenuates high glucose-induced MPC5 podocytes apoptosis by targeting braykinin B2 receptor. Exp Clin Endocrinol Diabetes. 127:387–395. 2019.PubMed/NCBI View Article : Google Scholar
28	Tu Q, Li Y, Jin J, Jiang X, Ren Y and He Q: Curcumin alleviates diabetic nephropathy via inhibiting podocyte mesenchymal transdifferentiation and inducing autophagy in rats and MPC5 cells. Pharm Biol. 57:778–786. 2019.PubMed/NCBI View Article : Google Scholar
29	Cao Y, Hao Y, Li H, Liu Q, Gao F, Liu W and Duan H: Role of endoplasmic reticulum stress in apoptosis of differentiated mouse podocytes induced by high glucose. Int J Mol Med. 33:809–816. 2014.PubMed/NCBI View Article : Google Scholar
30	Xi Z, Qiao Y, Wang J, Su H, Bao Z, Li H, Liao X and Zhong X: Gastrodin relieves inflammation injury induced by lipopolysaccharides in MRC-5 cells by up-regulation of miR-103. J Cell Mol Med. 24:1451–1459. 2020.PubMed/NCBI View Article : Google Scholar
31	Kim SH, Hwang JT, Park HS, Kwon DY and Kim MS: Capsaicin stimulates glucose uptake in C2C12 muscle cells via the reactive oxygen species (ROS)/AMPK/p38 MAPK pathway. Biochem Biophys Res Commun. 439:66–70. 2013.PubMed/NCBI View Article : Google Scholar
32	Chuang KC, Chen FW, Tsai MH and Shieh JJ: EGR-1 plays a protective role in AMPK inhibitor compound C-induced apoptosis through ROS-induced ERK activation in skin cancer cells. Oncol Lett. 21(304)2021.PubMed/NCBI View Article : Google Scholar
33	Bhattacharjee N, Barma S, Konwar N, Dewanjee S and Manna P: Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update. Eur J Pharmacol. 791:8–24. 2016.PubMed/NCBI View Article : Google Scholar
34	Papadopoulou-Marketou N, Chrousos GP and Kanaka-Gantenbein C: Diabetic nephropathy in type 1 diabetes: A review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev. 33(e2841)2017.PubMed/NCBI View Article : Google Scholar
35	Zhang XX, Kong J and Yun K: Prevalence of diabetic nephropathy among patients with type 2 diabetes mellitus in China: A meta-analysis of observational studies. J Diabetes Res. 2020(2315607)2020.PubMed/NCBI View Article : Google Scholar
36	Xiong Y and Zhou L: The signaling of cellular senescence in diabetic nephropathy. Oxid Med Cell Longev. 2019(7495629)2019.PubMed/NCBI View Article : Google Scholar
37	Bose M, Almas S and Prabhakar S: Wnt signaling and podocyte dysfunction in diabetic nephropathy. J Investig Med. 65:1093–1101. 2017.PubMed/NCBI View Article : Google Scholar
38	Tung CW, Hsu YC, Shih YH, Chang PJ and Lin CL: Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton). 23 (Suppl 4):S32–S37. 2018.PubMed/NCBI View Article : Google Scholar
39	Wang S, Zhao X, Yang S, Chen B and Shi J: Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway. Chem Biol Interact. 278:48–53. 2017.PubMed/NCBI View Article : Google Scholar
40	Zhao MX, Zhou B, Ling L, Xiong XQ, Zhang F, Chen Q, Li YH, Kang YM and Zhu GQ: Salusin-β contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death Dis. 8(e2690)2017.PubMed/NCBI View Article : Google Scholar
41	Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galán JE, Askenase PW and Flavell RA: Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 24:317–327. 2006.PubMed/NCBI View Article : Google Scholar
42	Pétrilli V, Dostert C, Muruve DA and Tschopp J: The inflammasome: A danger sensing complex triggering innate immunity. Curr Opin Immunol. 19:615–622. 2007.PubMed/NCBI View Article : Google Scholar
43	Lin TA, Wu VC and Wang CY: Autophagy in chronic kidney diseases. Cells. 8(61)2019.PubMed/NCBI View Article : Google Scholar
44	Kosuru R, Kandula V, Rai U, Prakash S, Xia Z and Singh S: Pterostilbene decreases cardiac oxidative stress and inflammation via activation of AMPK/Nrf2/HO-1 pathway in fructose-fed diabetic rats. Cardiovasc Drugs Ther. 32:147–163. 2018.PubMed/NCBI View Article : Google Scholar
45	Tanaka M, Kishimoto Y, Sasaki M, Sato A, Kamiya T, Kondo K and Iida K: Terminalia bellirica (Gaertn.) Roxb. extract and gallic acid attenuate LPS-induced inflammation and oxidative stress via MAPK/NF-κB and Akt/AMPK/Nrf2 pathways. Oxid Med Cell Longev. 2018(9364364)2018.PubMed/NCBI View Article : Google Scholar
46	Wang Y, Huang Y, Xu Y, Ruan W, Wang H, Zhang Y, Saavedra JM, Zhang L, Huang Z and Pang T: A Dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization. Antioxid Redox Signal. 28:141–163. 2018.PubMed/NCBI View Article : Google Scholar
47	Zeng HL, Huang SL, Xie FC, Zeng LM, Hu YH and Leng Y: Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice. Acta Pharmacol Sin. 36:343–352. 2015.PubMed/NCBI View Article : Google Scholar
48	Zhan X, Li J and Zhou T: Targeting Nrf2-mediated oxidative stress response signaling pathways as new therapeutic strategy for pituitary adenomas. Front Pharmacol. 12(565748)2021.PubMed/NCBI View Article : Google Scholar
49	Kim Y, Lee H, Kim SY and Lim Y: Effects of lespedeza bicolor extract on regulation of AMPK associated hepatic lipid metabolism in type 2 diabetic mice. Antioxidants (Basel). 8(599)2019.PubMed/NCBI View Article : Google Scholar
50	Huang Q, Wang T, Yang L and Wang HY: Ginsenoside Rb2 alleviates hepatic lipid accumulation by restoring autophagy via induction of Sirt1 and activation of AMPK. Int J Mol Sci. 18(1063)2017.PubMed/NCBI View Article : Google Scholar