SIRT1/NOX1 pathway mediated ameliorative effects of rosmarinic acid in folic acid-induced renal injury

Maryam Mottaghi , Akram Eidi, Fatemeh Heidari, Tahereh Komeili Movahhed, Azam Moslehi

Abstract


Background and purpose: Renal injury is a serious disorder that can be caused by some diseases or agents. Rosmarinic acid (RA) is a natural and safe compound with powerful antioxidant and anti-inflammatory properties. In this study, the ameliorative effects of RA were assayed in folic acid (FA)-induced renal injury by involving the SIRT1/NOX1 pathway.

Experimental approach: Thirty-six male C57/BL6 mice were divided into 6 groups (n = 6) including control, vehicle, FA, RA, FA + RA 50, and FA + RA 100. After 10 days, blood urea nitrogen (BUN), creatinine, and oxidative stress were measured. The expression of SIRT1 and NOX1 proteins was evaluated by western blot. Also, histopathological alterations were assayed by H&E and PAS staining methods.

Findings/Results: BUN and creatinine were significantly higher in the FA group compared to the control group; however, their levels decreased after RA treatment in both doses. A significant decrease was observed in swelling, necrosis, and desquamation of tubular epithelial cells in the FA + RA 50 and FA + RA 100 groups compared to the FA group. RA in the animals receiving FA increased SIRT1 expression and the levels of GSH and SOD compared to the FA group. RA in the animals receiving FA showed a significant decrease in NOX1 expression and MDA level compared to the FA group.

Conclusion and implications: The findings declared that the administration of RA has positive effects against renal damage induced by FA. The effect might result from involvement in the SIRT1/NOX1 pathway and thereby attenuation of oxidative stress.

 

 


Keywords


Folic acid; NOX1; Renal failure; Rosmarinic acid; SIRT1.

Full Text:

Untitled Untitled PDF

References


Mahadevan V. Anatomy of the kidney and ureter. Surgery (Oxford). 2019;37(7):359-364.DOI: 10.1016/j.mpsur.2019.04.005.

Koye DN, Magliano DJ, Nelson RG, Pavkov ME. The global epidemiology of diabetes and kidney disease. Adv Chronic Kidney Dis. 2018;25(2):121-132.DOI: 10.1053/j.ackd.2017.10.011.

Turgut F, Awad AS, Abdel-Rahman EM. Acute kidney injury: medical causes and pathogenesis. J Clin Med. 2023;12(1):375,1-11.DOI: 10.3390/jcm12010375.

Perazella MA, Rosner MH. Drug-induced acute kidney injury. Clin J Am Soc Nephrol. 2022;17(8):1220-1233.DOI: 10.2215/CJN.11290821.

Goossens JF, Thuru X, Bailly C. Properties and reactivity of the folic acid and folate photoproduct 6-formylpterin. Free Radic Biol Med. 2021;171:1-10.DOI: 10.1016/j.freeradbiomed.2021.05.002.

Brade W, Herken H, Merker HJ. Lesion and regeneration of renal tubule cells following administration of folic acid. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1969;262(2):228-250.PMID: 4239712.

Thabet RH, Alessa REM, Al-Smadi ZKK, Alshatnawi BSG, Amayreh BMI, Al-Dwaaghreh RBA, et al. Folic acid: friend or foe in cancer therapy. J Int Med Res. 2024;52(1):3000605231223064,1-19.DOI: 10.1177/03000605231223064.

Fink M, Henry M, Tange JD. Experimental folic acid nephropathy. Pathology. 1987;19(2):143-149.DOI: 10.3109/00313028709077125.

Samodelov SL, Gai Z, Kullak-Ublick GA, Visentin M. Renal reabsorption of folates: pharmacological and toxicological snapshots. Nutrients. 2019;11(10):2353,1-16.DOI: 10.3390/nu11102353.

Yan LJ. Folic acid‐induced animal model of kidney disease. Animal Model Exp Med. 2021;4(4):329-342.DOI: 10.1002/ame2.12194.

Bae CR, Kim Y, Kwon YG. CU06-1004 alleviates oxidative stress and inflammation on folic acid-induced acute kidney injury in mice. J Pharmacol Sci. 2024;154(2):77-85.DOI: 10.1016/j.jphs.2023.12.009.

Lin X, Fu B, Xiong Y, Xu S, Liu J, Zaky MY, et al. Folic acid ameliorates the declining quality of sodium fluoride-exposed mouse oocytes through the Sirt1/Sod2 pathway. Aging Dis. 2022;13(5):1471-1487.DOI: 10.14336/AD.2022.0217.

Rahman S, Islam R. Mammalian Sirt1: insights on its biological functions. Cell Commun Signal. 2011;9(1):1-8.DOI: 10.1186/1478-811X-9-11.

Yu J, Auwerx J. Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation. Pharmacol Res. 2010;62(1): 35-41.DOI: 10.1016/j.phrs.2009.12.006.

Salminen A, Kaarniranta K, Kauppinen A. Crosstalk between oxidative stress and SIRT1: impact on the aging process. Int J Mol Sci. 2013;14(2):3834-3859.DOI: 10.3390/ijms14023834.

Vermot A, Petit-Härtlein I, Smith SME, Fieschi F. NADPH oxidases (NOX): an overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants (Basel). 2021;10(6):890,1-55.DOI: 10.3390/antiox10060890.

Naderi R, Shirpoor A, Samadi M, Pourheydar B, Moslehi A. Tropisetron attenuates pancreas apoptosis in the STZ-induced diabetic rats: involvement of SIRT1/NF-κB signaling. Pharmacol Rep. 2020;72(6):1657-1665.DOI: 10.1007/s43440-020-00146-7.

Ruiz-Andres O, Sanchez-Niño MD, Cannata-Ortiz P, Ruiz-Ortega M, Egido J, Ortiz A, et al. Histone lysine crotonylation during acute kidney injury in mice. Dis Model Mech. 2016;9(6):633-645.DOI: 10.1242/dmm.024455.

Shi S, Chen Y, Luo Z, Nie G, Dai Y. Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy. Cell Commun Signal. 2023;21(1):1-20.DOI: 10.1186/s12964-023-01077-5.

Zhang W, Huang Q, Zeng Z, Wu J, Zhang Y, Chen Z. Sirt1 inhibits oxidative stress in vascular endothelial cells. Oxid Med Cell Longev. 2017;2017:1-8.DOI: 10.1155/2017/7543973.

Ding YW, Zhao GJ, Li XL, Hong GL, Li MF, Qiu QM, et al. SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro. Int J Mol Med. 2016;37(4):1049-1058.DOI: 10.3892/ijmm.2016.2503.

Komeili-Movahhed T, Bassirian M, Changizi Z, Moslehi A. SIRT1/NFκB pathway mediates anti-inflammatory and anti-apoptotic effects of rosmarinic acid on in a mouse model of nonalcoholic steatohepatitis (NASH). J Recept Signal Transduct Res. 2022;42(3):241-250.DOI: 10.1080/10799893.2021.1905665.

Hamidi-Zad Z, Moslehi A, Rastegarpanah M. Attenuating effects of allantoin on oxidative stress in a mouse model of nonalcoholic steatohepatitis: role of SIRT1/Nrf2 pathway. Res Pharm Sci. 2021;16(6):651-659.DOI: 10.4103/1735-5362.327511.

Heidari F, Komeili-Movahhed T, Hamidizad Z, Moslehi A. The protective effects of rosmarinic acid on ethanol-induced gastritis in male rats: antioxidant defense enhancement. Res Pharm Sci. 2021;16(3):305-314.DOI: 10.4103/1735-5362.314829.

Luo W, Tao Y, Chen S, Luo H, Li X, Qu S, et al. Rosmarinic acid ameliorates pulmonary ischemia/reperfusion injury by activating the PI3K/Akt signaling pathway. Front Pharmacol. 2022;13:860944,1-14.DOI: 10.3389/fphar.2022.860944.

Akhter J, Khan J, Baghel M, Beg MMA, Goswami P, Afjal MA, et al. NLRP3 inflammasome in rosmarinic acid-afforded attenuation of acute kidney injury in mice. Sci Rep. 2022;12(1):1-15.DOI: 10.1038/s41598-022-04785-z.

Hsieh YH, Tsai JP, Ting YH, Hung TW, Chao WW. Rosmarinic acid ameliorates renal interstitial fibrosis by inhibiting the phosphorylated-AKT mediated epithelial-mesenchymal transition in vitro and in vivo. Food Funct. 2022;13(8):4641-4652.DOI: 10.1039/D2FO00204C.

Noguchi-Shinohara M, Ono K, Hamaguchi T, Iwasa K, Nagai T, Kobayashi S, et al. Pharmacokinetics, safety and tolerability of Melissa officinalis extract which contained rosmarinic acid in healthy individuals: a randomized controlled trial. PloS one. 2015;10(5):e0126422,1-13.DOI: 10.1371/journal.pone.0126422.

Nie T, Cooper GJ. Mechanisms underlying the antidiabetic activities of polyphenolic compounds: a review. Front Pharmacol. 2021;12:3536,1-27.DOI: 10.3389/fphar.2021.798329.

Wang FX, Li HY, Li YQ, Kong LD. Can medicinal plants and bioactive compounds combat lipid peroxidation product 4-HNE-induced deleterious effects? Biomolecules. 2020;10(1):146,1-22.DOI: 10.3390/biom10010146.

Moslehi A, Komeili-Movahhed T, Ahmadian M, Ghoddoosi M, Heidari F. Chlorogenic acid attenuates liver apoptosis and inflammation in endoplasmic reticulum stress-induced mice. Iranian J Basic Med Sci. 2023;26(4):478-485.DOI: 10.22038/IJBMS.2023.66827.14659.

Zhang Y, Chen X, Yang L, Zu Y, Lu Q. Effects of rosmarinic acid on liver and kidney antioxidant enzymes, lipid peroxidation and tissue ultrastructure in aging mice. Food Funct. 2015;6(3):927-931.DOI: 10.1039/C4FO01051E.

Cook HC. Manual of histological demonstration techniques. London: Butterworths; 1974.

Hermsen M, de Bel T, Den Boer M, Steenbergen EJ, Kers J, Florquin S, et al. Deep learning-based histopathologic assessment of kidney tissue. J Am Soc Nephrol. 2019;30(10):1968-1979.DOI: 10.1681/ASN.2019020144.

Gupta A, Puri V, Sharma R, Puri S. Folic acid induces acute renal failure (ARF) by enhancing renal prooxidant state. Exp Toxicol Pathol. 2012;64(3):225-232.DOI: 10.1016/j.etp.2010.08.010.

Komeili-Movahhed T, Heidari F, Moslehi A. Chlorogenic acid alleviated testicular inflammation and apoptosis in tunicamycin induced endoplasmic reticulum stress. Physiol Int. 2023;110(1):19-33.DOI: 10.1556/2060.2023.00132.

Azab A, Fetouh FA, Albasha MO. Nephro-protective effects of curcumin, rosemary and propolis against gentamicin induced toxicity in guinea pigs: morphological and biochemical study. Am J Clin Med Res. 2014;2(2):28-35.DOI: 10.11648/j.ajcem.20140202.14.

Abduh MS, Alruhaimi RS, Alqhtani HA, Hussein OE, Abukhalil MH, Kamel EM, et al. Rosmarinic acid mitigates chlorpyrifos-induced oxidative stress, inflammation, and kidney injury in rats by modulating SIRT1 and Nrf2/HO-1 signaling. Life Sci. 2023;313:121281.DOI: 10.1016/j.lfs.2022.121281.

El-Desouky MA, Mahmoud MH, Riad BH, Taha YM. Nephroprotective effect of green tea, rosmarinic acid and rosemary on N-diethylnitrosamine initiated and ferric nitrilotriacetate promoted acute renal toxicity in Wistar rats. Interdiscip Toxicol. 2019;12(2):98-110.DOI: 10.2478/intox-2019-0012.

Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, et al. Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor α in mammalian retinal pigment epithelium. J Biol Chem. 2000;275(27):20676-20684.DOI: 10.1074/jbc.M002328200.

Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014;533(1):11-20.DOI: 10.1016/j.gene.2013.09.063.

Miguel V, Ramos R, García-Bermejo L, Rodríguez-Puyol D, Lamas S. The program of renal fibrogenesis is controlled by microRNAs regulating oxidative metabolism. Redox Biol. 2021;40: 101851,1-11.DOI: 10.1016/j.redox.2020.101851.

Whitaker RM, Wills LP, Stallons LJ, Schnellmann RG. cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury. J Pharmacol Exp Ther. 2013;347(3):626-634.DOI: 10.1124/jpet.113.208017.

Ruiz-Andres O, Suarez-Alvarez B, Sánchez-Ramos C, Monsalve M, Sanchez-Niño MD, Ruiz-Ortega M, et al. The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. Kidney Int. 2016;89(2): 399-410.DOI: 10.1038/ki.2015.332.

Fontecha‐Barriuso M, Martín‐Sánchez D, Martinez‐Moreno JM, Carrasco S, Ruiz‐Andrés O, Monsalve M, et al. PGC‐1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI. J Pathol. 2019;249(1):65-78.DOI: 10.1002/path.5282.

Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25(1):27-42.DOI: 10.1016/j.cmet.2016.08.009.

Yan LJ, Rajasekaran NS, Sathyanarayanan S, Benjamin IJ. Mouse HSF1 disruption perturbs redox state and increases mitochondrial oxidative stress in kidney. Antioxid Redox Signal. 2005;7(3-4):465-471.DOI: 10.1089/ars.2005.7.465.

Hwang SY, Siow YL, Au-Yeung KK, House J, O K. Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney. Am J Physiol Renal Physiol. 2011;300(1):F189-F198.DOI: 10.1152/ajprenal.00272.2010.

Gallego-Lopez MDC, Ojeda ML, Romero-Herrera I, Nogales F, Carreras O. Folic acid homeostasis and its pathways related to hepatic oxidation in adolescent rats exposed to binge drinking. J Antioxidants. 2022;11(2):362,1-22.DOI: 10.3390/antiox11020362.

Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol. 2024;98(5):1323-1367.DOI: 10.1007/s00204-024-03696-4.

Lee OYA, Wong ANN, Ho CY, Tse KW, Chan AZ, Leung GPH, et al. Potentials of natural antioxidants in reducing inflammation and oxidative stress in chronic kidney disease. Antioxidants (Basel). 2024;13(6):751,1-38.DOI: 10.3390/antiox13060751.

Nadeem M, Imran M, Aslam Gondal T, Imran A, Shahbaz M, Muhammad Amir R, et al. Therapeutic potential of rosmarinic acid: a comprehensive review. Appl Sci. 2019;9(15):3139,1-23.DOI: 10.3390/app9153139.

Noor S, Mohammad T, Rub MA, Raza A, Azum N, Yadav DK, et al. Biomedical features and therapeutic potential of rosmarinic acid. Arch Pharm Res. 2022;45(4):205-228.DOI: 10.1007/s12272-022-01378-2.

Simone S, Rascio F, Castellano G, Divella C, Ditonno P, Battaglia M, et al. Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury. Free Radic Biol Med. 2014;74:263-273.DOI: 10.1016/j.freeradbiomed.2014.07.003.

Aranda-Rivera AK, Cruz-Gregorio A, Aparicio-Trejo OE, Pedraza-Chaverri J. Mitochondrial redox signaling and oxidative stress in kidney diseases. Biomolecules. 2021;11(8):1144,1-29.DOI: 10.3390/biom11081144.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.