Protective Effect of Resveratrol on Exercise-induced Kidney Injury in Rats by Regulating Keap1-Nrf2 Signaling Pathway

ZHOU Haitao; HU Ge; ZHANG Jing; ZHOU Qiyun; QIN Fei

doi:10.13386/j.issn1002-0306.2024060169

Volume 46 Issue 8

Apr. 2025

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Science and Technology of Food Industry > 2025 > 46(8): 362-370. > DOI: 10.13386/j.issn1002-0306.2024060169

ZHOU Haitao, HU Ge, ZHANG Jing, et al. Protective Effect of Resveratrol on Exercise-induced Kidney Injury in Rats by Regulating Keap1-Nrf2 Signaling Pathway[J]. Science and Technology of Food Industry, 2025, 46(8): 362−370. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2024060169.

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Protective Effect of Resveratrol on Exercise-induced Kidney Injury in Rats by Regulating Keap1-Nrf2 Signaling Pathway

1.
Institute of Physical Exercise and Health, Beijing Union University, Beijing 100101, China
2.
School of Physical Education, Changzhou University, Changzhou 213164, China
3.
College of Biochemical Engineering, Beijing Union University, Beijing 100023, China

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Received Date: June 11, 2024
Available Online: February 17, 2025

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Abstract

Abstract

Objective: To investigate the protective mechanism of resveratrol on exercise-induced kidney injury in rats. Methods: Thirty-two 7-week-old SPF-grade male SD rats were randomly assigned to four groups: control group (CONT, n=8), resveratrol group (RESV, n=8), exercise-induced kidney injury model group (EIKIM, n=8), and resveratrol-treated exercise-induced kidney injury group (REIKIM, n=8). Rats in groups EIKIM and REIKIM underwent high-intensity treadmill training to establish a model of exercise-induced kidney injury. During the four-week training, rats in groups RESV and REIKIM were administered resveratrol solution intragastrically at a dosage of 150 mg/kg·bw and a volume of 5 mL/kg, 1 h prior to each training session, and the remaining rats received an equal volume of solvent. Blood and kidney samples were obtained 24 h post the final training session. Kidney morphology was assessed using HE staining. Levels of serum creatinine (Cr) and urea nitrogen (UN), renal kelch-like ECH-associated protein-1 (Keap1), nuclear factor-E2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) mRNA and protein expression levels, phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) protein expression level, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GSH-ST) activity, levels of malondialdehyde (MDA), reactive oxygen species (ROS), apoptosis, B cell lymphoma-2 protein (Bcl-2), bcl-2-associated X protein (Bax), cysteinyl aspartate specific proteinase-9 (Caspase-9), and cysteinyl aspartate specific proteinase-3 (Caspase-3) protein expression were detected. Results: After 4 weeks of high-intensity treadmill training, significant renal pathological changes of rats were observed in group EIKIM compared to group CONT, with increased levels of serum Cr and UN, renal Keap1 mRNA and protein expression, MDA, ROS, apoptosis, Bax, Caspase-9, Caspase-3 protein expression and Bax/Bcl-2 ratio (P<0.01), and decreased levels of renal Nrf2, NQO1, HO-1 mRNA and protein expression, SOD CAT and GSH-ST activity, p-Nrf2, Bcl-2 protein expression and p-Nrf2/Nrf2 ratio (P<0.01). In contrast, after 4 weeks of resveratrol treatment, rats in group REIKIM exhibited significant improvements in renal pathology compared to group EIKIM, with decreased levels of serum Cr and UN, renal Keap1 mRNA and protein expression, MDA, ROS, apoptosis, Bax, Caspase-9, Caspase-3 protein expression and Bax/Bcl-2 ratio (P<0.05 or P<0.01), and increased levels of renal Nrf2, NQO1, HO-1 mRNA and protein expression, SOD, CAT and GSH-ST activity, p-Nrf2, Bcl-2 protein expression and p-Nrf2/Nrf2 ratio (P<0.05 or P<0.01). Conclusions: Resveratrol can activate the Keap1-Nrf2 signaling pathway of rats subjected to high-intensity exercise effectively, suppress oxidative stress and apoptosis, thereby protecting the integrity of renal structure and function.

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References

[1]	KUO C P, TSAI M T, LEE K H, et al. Dose-response effects of physical activity on all-cause mortality and major cardiorenal outcomes in chronic kidney disease[J]. European Journal of Preventive Cardiology,2022,29(3):452−461. doi: 10.1093/eurjpc/zwaa162
[2]	陈丽娜, 周刚, 吴乐, 等. 力竭运动对大鼠肾脏的影响[J]. 中国康复理论与实践,2016,22(7):789−792. [CHEN L N, ZHOU G, WU L, et al. Effect of exhaustive exercise on kidney in rats[J]. Chinese Journal of Rehabilitation Theory and Practice,2016,22(7):789−792.] doi: 10.3969/j.issn.1006-9771.2016.07.010 CHEN L N, ZHOU G, WU L, et al. Effect of exhaustive exercise on kidney in rats[J]. Chinese Journal of Rehabilitation Theory and Practice, 2016, 22（7）: 789−792. doi: 10.3969/j.issn.1006-9771.2016.07.010
[3]	胡戈, 曹卉, 周海涛, 等. 姜黄素对过度训练大鼠肾脏细胞凋亡的调控作用及其机制[J]. 中国应用生理学杂志,2018,34(6):513−518,583−584. [HU G, CAO H, ZHOU H T, et al. Regulatory effect of curcumin on renal apoptosis and its mechanism in overtraining rats[J]. Chinese Journal of Applied Physiology,2018,34(6):513−518,583−584.] HU G, CAO H, ZHOU H T, et al. Regulatory effect of curcumin on renal apoptosis and its mechanism in overtraining rats[J]. Chinese Journal of Applied Physiology, 2018, 34（6）: 513−518,583−584.
[4]	BAIRD L, YAMAMOTO M. The molecular mechanisms regulating the Keap1-Nrf2 Pathway[J]. Molecular and Cellular Biology,2020,40(13):e00099−20.
[5]	NITURE S K, JAISWAL A K. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis[J]. The Journal of Biological Chemistry,2012,287(13):9873−9886. doi: 10.1074/jbc.M111.312694
[6]	FARKHONDEH T, FOLGADO S L, POURBAGHER-SHAHRI AM, et al. The therapeutic effect of resveratrol:Focusing on the Nrf2 signaling pathway[J]. Biomedicine & Pharmacotherapy,2020,127:110234.
[7]	王引, 张兰威. 益生菌联合白藜芦醇对小鼠慢性酒精性肝损伤的改善作用及机制研究[J]. 食品工业科技,2022,43(5):374−380. [WANG Y, ZHANG L W. Ameliorative effect and mechanism of probiotics combined with resveratrol on chronic alcoholic liver injury in mice[J]. Science and Technology of Food Industry,2022,43(5):374−380.] WANG Y, ZHANG L W. Ameliorative effect and mechanism of probiotics combined with resveratrol on chronic alcoholic liver injury in mice[J]. Science and Technology of Food Industry, 2022, 43（5）: 374−380.
[8]	张琳, 熊正英, 郝选明, 等. 白藜芦醇对大强度运动大鼠肾脏功能的保护作用[J]. 天津体育学院学报,2011,26(3):208−210. [ZHANG L, XIONG Z Y, HAO X M. Protective effects of resveratrol on kidney in intensive exercise rats[J]. Journal of Tianjin University of Sport,2011,26(3):208−210.] doi: 10.3969/j.issn.1005-0000.2011.03.006 ZHANG L, XIONG Z Y, HAO X M. Protective effects of resveratrol on kidney in intensive exercise rats[J]. Journal of Tianjin University of Sport, 2011, 26（3）: 208−210. doi: 10.3969/j.issn.1005-0000.2011.03.006
[9]	胡戈, 马欣雨, 秦菲, 等. 白藜芦醇对大鼠运动性肝损伤的保护作用[J]. 中国实验动物学报,2023,31(6):763−769. [HU G, MA X Y, QIN F, et al. Protective effect of resveratrol on exercise-induced liver injury in rats[J]. Acta Laboratorium Animalis Scientia Sinica,2023,31(6):763−769.] doi: 10.3969/j.issn.1005-4847.2023.06.008 HU G, MA X Y, QIN F, et al. Protective effect of resveratrol on exercise-induced liver injury in rats[J]. Acta Laboratorium Animalis Scientia Sinica, 2023, 31（6）: 763−769. doi: 10.3969/j.issn.1005-4847.2023.06.008
[10]	李方, 曹建民, 王传军, 等. 白藜芦醇通过调节SIRT1/NF-κB通路减轻力竭训练致大鼠肾的炎症反应[J]. 中国生物化学与分子生物学报,2019,35(7):773−779. [LI F, CAO J M, WANG C J, et al. Resveratrol reduces renal inflammatory response induced by exhaustive exercise in rats by regulating SIRT1/NF-κB pathway[J]. Chinese Journal of Biochemistry and Molecular Biology,2019,35(7):773−779.] LI F, CAO J M, WANG C J, et al. Resveratrol reduces renal inflammatory response induced by exhaustive exercise in rats by regulating SIRT1/NF-κB pathway[J]. Chinese Journal of Biochemistry and Molecular Biology, 2019, 35（7）: 773−779.
[11]	赵昆, 黎璞. 白藜芦醇对力竭训练动物能量代谢和抗氧化功能的影响[J]. 基因组学与应用生物学,2020,39(2):902−908. [ZHAO K, LI P. Effects of resveratrol on energy metabolism and antioxidant function in exhausted training animals[J]. Genomics and Applied Biology,2020,39(2):902−908.] ZHAO K, LI P. Effects of resveratrol on energy metabolism and antioxidant function in exhausted training animals[J]. Genomics and Applied Biology, 2020, 39（2）: 902−908.
[12]	DOLINSKY V W, JONES K E, SIDHU R S, et al. Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats[J]. The Journal of Physiology,2012,590(11):2783−2799. doi: 10.1113/jphysiol.2012.230490
[13]	MARSLAND M, DOWDELL A, JIANG C C, et al. Expression of NGF/proNGF and their receptors TrkA, p75NTR and sortilin in melanoma[J]. International Journal of Molecular Sciences,2022,23(8):4260. doi: 10.3390/ijms23084260
[14]	李郭锦, 张路, 穆长征, 等. 大鼠肾缺血再灌注损伤程序性坏死的形态学观察[J]. 解放军医学杂志,2013,38(10):792−795. [LI G J, ZHANG L, MU C Z, et al. Morphological observation of necroptosis after renal ischemia-reperfusion injury in rats[J]. Medical Journal of Chinese People's Liberation Army,2013,38(10):792−795.] doi: 10.11855/j.issn.0577-7402.2013.10.02 LI G J, ZHANG L, MU C Z, et al. Morphological observation of necroptosis after renal ischemia-reperfusion injury in rats[J]. Medical Journal of Chinese People's Liberation Army, 2013, 38（10）: 792−795. doi: 10.11855/j.issn.0577-7402.2013.10.02
[15]	WANG Z S, ZHOU H H, HAN Q, et al. Effects of grape seed proanthocyanidin B2 pretreatment on oxidative stress and renal tubular epithelial cell apoptosis after renal ischemia reperfusion in mice[J]. Acta Cirurgica Brasileira,2020,35(8):e202000802. doi: 10.1590/s0102-865020200080000002
[16]	LI M, NING J, HUANG H, et al. Allicin protects against renal ischemia-reperfusion injury by attenuating oxidative stress and apoptosis[J]. International Urology Nephrology,2022,54(7):1761−1768. doi: 10.1007/s11255-021-03014-2
[17]	牛衍龙, 曹建民, 周海涛, 等. 6周大强度训练对大鼠肾功能的影响及其机制[J]. 中国应用生理学杂志,2018,34(1):65−68,73. [NIU Y L, CAO J M, ZHOU H T, et al. Effects and mechanisms of 6-week intensive training on renal function in rats[J]. Chinese Journal of Applied Physiology,2018,34(1):65−68,73.] doi: 10.12047/j.cjap.5641.2018.017 NIU Y L, CAO J M, ZHOU H T, et al. Effects and mechanisms of 6-week intensive training on renal function in rats[J]. Chinese Journal of Applied Physiology, 2018, 34（1）: 65−68,73. doi: 10.12047/j.cjap.5641.2018.017
[18]	刘佩佳, 彭洪泉, 郭兴华, 等. 验证四种基于肌酐的肾小球滤过率估算方程的性能[J]. 中山大学学报(医学科学版),2022,43(4):621−630. [LIU P J, PENG H Q, GUO X H, et al. Comparative performance of four creatinine-based gfr estimating equations[J]. Journal of Sun Yat-Sen University (Medical Sciences),2022,43(4):621−630.] LIU P J, PENG H Q, GUO X H, et al. Comparative performance of four creatinine-based gfr estimating equations[J]. Journal of Sun Yat-Sen University （Medical Sciences）, 2022, 43（4）: 621−630.
[19]	RASHID H, JALI A, AKHTER M S, et al. Molecular mechanisms of oxidative stress in acute kidney injury:targeting the loci by resveratrol[J]. International Journal of Molecular Sciences,2023,25(1):3. doi: 10.3390/ijms25010003
[20]	WANG Y, FENG F L, LIU M N, et al. Resveratrol ameliorates sepsis-induced acute kidney injury in a pediatric rat model via Nrf2 signaling pathway[J]. Experimental and Therapeutic Medicine,2018,16(4):3233−3240.
[21]	NGO V, DUENNWALD ML. Nrf2 and oxidative stress:A general overview of mechanisms and implications in human disease[J]. Antioxidants (Basel),2022,11(12):2345. doi: 10.3390/antiox11122345
[22]	PIZZINO G, IRRERA N, CUCINOTTA M, et al. Oxidative stress:harms and benefits for human health[J]. Oxidative Medicine and Cellular Longevity,2017,2017:8416763. doi: 10.1155/2017/8416763
[23]	SIMON H U, HAJ-YEHIA A, LEVI-SCHAFFER F. Role of reactive oxygen species (ROS) in apoptosis induction[J]. Apoptosis,2000,5(5):415−418. doi: 10.1023/A:1009616228304
[24]	VILLALPANDO-RODRIGUEZ GE, GIBSON SB. Reactive oxygen species (ROS) Regulates different types of cell death by acting as a rheostat[J]. Oxidative Medicine and Cellular Longevity,2021,2021:9912436. doi: 10.1155/2021/9912436
[25]	van OPDENBOSCH N, LAMKANFI M. Caspases in cell death, inflammation, and disease[J]. Immunity,2019,50(6):1352−1364. doi: 10.1016/j.immuni.2019.05.020
[26]	MUSHTAQ A U, ÅDÉN J, ALI K, et al. Domain-specific insight into the recognition of BH3-death motifs by the pro-survival Bcl-2 protein[J]. Biophysical Journal,2022,121(23):4517−4525. doi: 10.1016/j.bpj.2022.10.041
[27]	YI J, YANG X, ZHENG L, et al. Photoactivation of hypericin decreases the viability of RINm5F insulinoma cells through reduction in JNK/ERK phosphorylation and elevation of caspase-9/caspase-3 cleavage and Bax-to-Bcl-2 ratio[J]. Bioscience Reports,2015,35(3):e00195. doi: 10.1042/BSR20150028
[28]	PRIANTE G, GIANESELLO L, CEOL M, et al. Cell death in the kidney[J]. International Journal of Molecular Sciences,2019,20(14):3598. doi: 10.3390/ijms20143598
[29]	KIM E N, LIM J H, KIM MY, et al. Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury[J]. Aging (Albany, NY),2018,10(1):83−99. doi: 10.18632/aging.101361
[30]	LI J W, LI L, WANG S, et al. Resveratrol alleviates inflammatory responses and oxidative stress in rat kidney ischemia-reperfusion injury and H₂O₂-induced NRK-52E cells via the Nrf2/TLR4/NF-κB Pathway[J]. Cell and Physiology Biochemistry and Biophysical Journal,2018,45(4):1677−1689. doi: 10.1159/000487735