Objective: To investigate the protective effect of ursolic acid (UA) on isoproterenol (ISO)-induced kidney injury in mice.
Methods: Four groups of mice were used: Group I (Control) received phosphate-buffered saline i.p. for four weeks; Group II (ISO alone) was administered ISO (10 mg/kg i.p.) daily for four weeks to induce kidney injury; Group III (ISO+UA) was pretreated with UA (40 mg/kg i.p.) once daily, followed by ISO (10 mg/kg i.p.) once daily for four weeks; Group IV (UA alone) received UA (40 mg/kg i.p.) daily for four weeks. Markers of oxidative stress, inflammation, and apoptosis were analyzed, and the protein expression of p-PI3K and p-Akt was determined.
Results: UA treatment significantly alleviated ISO-induced kidney injury, evidenced by lowered levels of malondialdehyde, IL-6, TNF-α and IL-Iβ, downregulated expression of cleaved caspase-3 and PARP, and upregulated expression of Bcl-2 and Bcl-xL. It also activated the PI3K/Akt pathway.
Conclusions: UA demonstrates renoprotective effects against ISO-induced kidney injury by reducing oxidative stress, inflammation, and apoptosis, likely through PI3K/Akt pathway activation. These findings suggest that UA may serve as a potential therapeutic agent for renal diseases linked to inflammation and oxidative stress, meriting further exploration for clinical applications.
Conflict of interest statement
The author declares no conflict of interest.
Funding
The author acknowledged the Deanship of Scientific Research, Vice Presidency at King Faisal University, Saudi Arabia for financial support under the annual funding track [Grant A129].
Data availability statement
The data supporting the findings of this study are available from the corresponding author upon request.
Publisher’s note
The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
| [1] |
Grant MK, Abdelgawad IY, Lewis CA, Seelig D, Zordoky BN. Lack of sexual dimorphism in a mouse model of isoproterenol-induced cardiac dysfunction. PLoS One 2020; 15(7). doi: 10.1371/journal.pone.0232507.
|
| [2] |
Garnier A, Leroy J, Deloménie C, Mateo P, Viollet B, Veksler V, et al. Modulation of cardiac cAMP signaling by AMPK and its adjustments in pressure overload-induced myocardial dysfunction in rat and mouse. PLoS One 2023; 18(9). doi: 10.1371/journal.pone.0292015.
|
| [3] |
Farag MM, Khalifa AA, Elhadidy WF, Rashad RM. Thymoquinone dose-dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulations of oxidative stress, inflammation, apoptosis, autophagy, and fibrosis. Naunyn Schmiedebergs Arch Pharmacol 2021; 394(8): 1787-1801.
|
| [4] |
Zhou W, Fu Y, Xu JS. Sophocarpine alleviates isoproterenol-induced kidney injury by suppressing inflammation, apoptosis, oxidative stress and fibrosis. Molecules 2022; 27(22): 7868.
|
| [5] |
Chisty TTE, Sarif S, Jahan I, Ismail IN, Chowdhury FI, Siddiqua S, et al. Protective effects of L-carnitine on isoprenaline-induced heart and kidney dysfunctions: Modulation of inflammation and oxidative stress-related gene expression in rats. Heliyon 2024; 10(3). doi: 10.1016/j.heliyon.2024.e25057.
|
| [6] |
Johnson AC, Zager RA. Catalytic iron mediated renal stress responses during experimental cardiorenal syndrome 1 (“CRS-1”). Transl Res 2021; 237: 53-62.
|
| [7] |
Liu P, Xue Y, Zheng B, Liang Y, Zhang J, Shi J, et al. Crocetin attenuates the oxidative stress, inflammation and apoptosisin arsenic trioxide-induced nephrotoxic rats: Implication of PI3K/AKT pathway. Int Immunopharmacol 2020; 88. doi: 10.1016/j.intimp.2020.106959.
|
| [8] |
Chen H, Zhang Y, Zou M, Qi X, Xu S. Bisphenol A aggravates renal apoptosis and necroptosis in selenium-deficient chickens via oxidative stress and PI3K/AKT pathway. J Cell Physiol 2022; 237(8): 3292-3304.
|
| [9] |
Zheng HL, Zhang HY, Zhu CL, Li HY, Cui S, Jin J, et al. L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling. Acta Pharmacol Sin 2021; 42(1): 77-87.
|
| [10] |
Ma X, Ma J, Leng T, Yuan Z, Hu T, Liu Q, et al. Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention. Ren Fail 2023; 45(1). doi: 10.1080/0886022X.2022.2146512.
|
| [11] |
Rajendran P, Renu K, Abdallah BM, Ali EM, Veeraraghavan VP, Sivalingam K, et al. Nimbolide: Promising agent for prevention and treatment of chronic diseases (recent update). Food Nutr Res 2024; 68. doi: 10.29219/fnr.v68.9650.
|
| [12] |
Rajendran P. Unveiling the power of flavonoids: A dynamic exploration of their impact on cancer through matrix metalloproteinases regulation. Biomed (Taipei) 2024; 14(2): 12-28.
|
| [13] |
Kang HG, Lee HK, Cho KB, Park SI. A review of natural products for prevention of acute kidney injury. Medicina 2021; 57(11): 1266.
|
| [14] |
Shi Y, Liu J, Hou M, Tan Z, Chen F, Zhang J, et al. Ursolic acid improves necroptosis via STAT3 signaling in intestinal ischemia/reperfusion injury. Int Immunopharmcol 2024; 138. doi: 10.1016/j.intimp.2024.112463.
|
| [15] |
Wu X, Li H, Wan Z, Wang R, Liu J, Liu Q, et al. The combination of ursolic acid and empagliflozin relieves diabetic nephropathy by reducing inflammation, oxidative stress and renal fibrosis. Biomed Pharmacother 2021; 144. doi: 10.1016/j.biopha.2021.112267.
|
| [16] |
Liu Y, Zheng JY, Wei ZT, Liu SK, Sun JL, Mao YH, et al. Therapeutic effect and mechanism of combination therapy with ursolic acid and insulin on diabetic nephropathy in a type I diabetic rat model. Front Pharm 2022; 13. doi: 10.3389/fphar.2022.969207.
|
| [17] |
Saravanan R, Pugalendi V. Impact of ursolic acid on chronic ethanol-induced oxidative stress in the rat heart. Pharmacol Rep 2006; 58(1): 4147.
|
| [18] |
Rong ZJ, Chen M, Cai HH, Liu GH, Chen JB, Wang H, et al. Ursolic acid molecules dock MAPK1 to modulate gut microbiota diversity to reduce neuropathic pain. Neuropharmacol 2024; 252. doi: 10.1016/j.neuropharm.2024.109939.
|
| [19] |
Rajendran P, Alzahrani AM, Priya Veeraraghavan V, Ahmed EA. Anti-apoptotic effect of flavokawain A on ochratoxin-A-induced endothelial cell injury by attenuation of oxidative stress via PI3K/AKT-mediated Nrf2 signaling cascade. Toxins 2021; 13(11): 745.
|
| [20] |
Musthafa QA, Abdul Shukor MF, Ismail NAS, Mohd Ghazi A, Mohd Ali R, M Nor IF, et al. Oxidative status and reduced glutathione levels in premature coronary artery disease and coronary artery disease. Free Radic Res 2017; 51: 787-798.
|
| [21] |
Li J, Thangaiyan R, Govindasamy K, Wei J. Anti-inflammatory and anti-apoptotic effect of zingiberene on isoproterenol-induced myocardial infarction in experimental animals. Human Exp Toxicol 2021; 40(6): 915-927.
|
| [22] |
Yang Y, Xia Z, Xu C, Zhai C, Yu X, Li S. Ciprofol attenuates the isoproterenol-induced oxidative damage, inflammatory response and cardiomyocyte apoptosis. Front Pharmacol 2022; 13. doi: 10.3389/fphar.2022.1037151.
|
| [23] |
Obeidat HM, Althunibat OY, Alfwuaires MA, Aladaileh SH, Algefare AI, Almuqati AF, et al. Cardioprotective effect of taxifolin against isoproterenol-induced cardiac injury through decreasing oxidative stress, inflammation, and cell death, and activating Nrf2/HO-1 in mice. Biomolecules 2022; 12(11): 1546.
|
| [24] |
Abukhalil MH, Hussein OE, Aladaileh SH, Althunibat OY, Al-Amarat W, Saghir SA, et al. Visnagin prevents isoproterenol-induced myocardial injury by attenuating oxidative stress and inflammation and upregulating Nrf 2 signaling in rats. J Biochem Mol Toxicol 2021; 35(11). doi: 10.1002/jbt.22906.
|
| [25] |
Shi Y, Leng Y, Liu D, Liu X, Ren Y, Zhang J, et al. Research advances in protective effects of ursolic acid and oleanolic acid against gastrointestinal diseases. Am J Chin Med 2021; 49(2): 413-435.
|
| [26] |
Nguyen HN, Ullevig SL, Short JD, Wang L, Ahn YJ, Asmis R. Ursolic acid and related analogues: Triterpenoids with broad health benefits. Antioxidants 2021; 10(8): 1161.
|
| [27] |
Sun Q, He M, Zhang M, Zeng S, Chen L, Zhou L, et al. Ursolic acid: A systematic review of its pharmacology, toxicity and rethink on its pharmacokinetics based on PK-PD model. Fitoterapia 2020; 147. doi: 10.1016/j.fitote.2020.104735.
|
| [28] |
Liu CH, Wong SH, Tai CJ, Tai CJ, Pan YC, Hsu HY, et al. Ursolic acid and its nanoparticles are potentiators of oncolytic measles virotherapy against breast cancer cells. Cancers 2021; 13(1): 136.
|
| [29] |
Erdmann J, Kujaci ski M, Wici ski M. Beneficial effects of ursolic acid and its derivatives—focus on potential biochemical mechanisms in cardiovascular conditions. Nutrients 2021; 13(11): 3900.
|
| [30] |
Tripathi P, Alshahrani S. Mitigation of IL-1β IL-6, TNF-α and markers of apoptosis by ursolic acid against cisplatin-induced oxidative stress and nephrotoxicity in rats. Hum Exp Toxicol 2021; 40(12_suppl): S397-S405.
|
| [31] |
Viswanadha VP, Dhivya V, Beeraka NM, Huang CY, Gavryushova LV, Minyaeva NN, et al. The protective effect of piperine against isoproterenol-induced inflammation in experimental models of myocardial toxicity. Eur J Pharmacol 2020; 885. doi: 10.1016/j.ejphar.2020.173524.
|
| [32] |
Chen WY, Wang HW, Yao S, Zhou Y, Liu SC, Shen XL. The natural sources, extraction, and nephroprotective function of oleanolic acid and ursolic acid: A review. Food Health 2024; 6:13.
|
| [33] |
Liu G, Qin P, Cheng X, Wu L, Wang R, Gao W. Ursolic acid: Biological functions and application in animal husbandry. Front Vet Sci 2023; 10. doi: 10.3389/fvets.2023.1251248.
|
| [34] |
Signorini L, Granata S, Lupo A, Zaza G. Naturally occurring compounds: New potential weapons against oxidative stress in chronic kidney disease. Int J Mol Sci 2017; 18(7): 1481.
|
| [35] |
Karthik M, Manoharan S, Muralinaidu R. Ursolic acid-loaded chitosan nanoparticles suppress 7, 12-dimethylbenz (a) anthracene-induced oral tumor formation through their antilipid peroxidative potential in golden Syrian hamsters. Naunyn Schmiedebergs Arch Pharmacol 2023; 396(11): 3061-3074.
|
| [36] |
Luan M, Wang H, Wang J, Zhang X, Zhao F, Liu Z, et al. Advances in anti-inflammatory activity, mechanism and therapeutic application of ursolic acid. Mini Rev Med Chem 2022; 22(3): 422-436.
|
| [37] |
Sun X, Chen X, Wang S, Zhang J, Wu B, Qin G. Protective effect of ursolic acid in Prunella vulgaris L. on LPS-induced asthenozoospermia via Bcl-2/Bax apoptosis signaling pathway. Curr Pharm Biotechnol 2021; 22(14): 1953-1959.
|
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