Valproate is known to disturb the kidney function, and high doses or prolonged intake may cause serum ion imbalance, kidney tubular acidosis, proteinuria, hyperuricosuria, polyuria, polydipsia, and dehydration. The aim of this in vivo study was to see whether naringin would counter the adverse effects of high-dose valproate in C57Bl/6 mice and to which extent. As expected, valproate (150 mg/kg bw a day for 10 days) caused serum hyperkalaemia, more in male than female mice. Naringin reversed (25 mg/kg bw a day for 10 days) the hyperkalaemia and activated antioxidative defence mechanisms (mainly catalase and glutathione), again more efficiently in females. In males naringin combined with valproate was not as effective and even showed some prooxidative effects.

Valproat je jedan od najčešće primjenjivanih antiepileptika, a poznato je da prouzročuje poremećenu funkciju proksimalnih bubrežnih tubula. Fiziološki poremećaji i nefrotoksični učinci u nekih bolesnika nakon visokih doza ili produljenog uzimanja valproata uključuju disbalans iona u serumu, bubrežnu tubularnu acidozu, proteinuriju, hiperurikozuriju, poliuriju, polidipsiju, dehidraciju i druge poremećaje. U okviru ovog eksperimentalnog rada primijenili smo visoke doze valproata i združeni tretman valproata i naringina u C57Bl/6 miševa. Naringin je poznati antioksidans i protuupalna flavonoidna molekula iz citrusnog voća. Cilj rada bio je utvrditi mogu li biološka svojstva naringina umanjiti štetne učinke na bubrege nakon tretmana valproatom. Valproat je in vivo prouzročio serumsku hiperkalijemiju, izraženiju u mužjaka nego u ženki miševa. Hiperkalijemija prouzročena valproatom bila je ublažena naringinom, a antioksidacijski obrambeni mehanizmi (uglavnom katalaza i smanjena glutationacija) bili su aktivirani, više u ženki. U mužjaka, zajednički tretman valproatom i naringinom nije bio tako učinkovit, a rezultati upućuju na moguće prooksidacijsko djelovanje u bubrežnom tkivu kada se obje tvari primjenjuju zajedno.

Czech Academy of Sciences Institute of Physiology Prague Czechia

Genos Ltd Glycoscience Research Laboratory Zagreb Croatia

Regionshospitalet Gødstrup Herning Denmark

University of Zagreb Faculty of Food Technology and Biotechnology Zagreb Croatia

University of Zagreb Faculty of Science Zagreb Croatia

Zobrazit více v PubMed

Anguissola G, Leu D, Simonetti GD, Simonetti BG, Lava SAG, Milani GP, Bianchetti MG, Scoglio M Kidney tubular injury induced by valproic acid: systematic literature review Pediatr Nephrol. 2023;38:1725. doi: 10.1007/s00467-022-05869-8. . . ; : –. . doi: PubMed DOI PMC

Karatzas A, Paridis D, Kozyrakis D, Tzortzis V, Samarinas M, Dailiana Z, Karachalios T Fanconi syndrome in the adulthood. The role of early diagnosis and treatment J Musculoskelet Neuronal Interact. 2017;17:303. . . ; : –. . PMCID: PMC5749037. PubMed PMC

Heidari R, Jafari F, Khodaei F, ShiraziYeganeh B, Niknahad H Mechanism of valproic acid induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney Nephrology. 2018;23:351. doi: 10.1111/nep.13012. . . ; : –. . doi: PubMed DOI

Ono H Sodium valproate-induced Fanconi syndrome in two severely disabled patients receiving carnitine supplementation Clin Exp Nephrol. 2019;23:148. doi: 10.1007/s10157-018-1581-3. . . ; : –. . doi: PubMed DOI

Gezginci-Oktayoglu S, Turkyilmaz IB, Ercin M, Yanardag R, Bolkent S Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties Protoplasma. 2016;253:127. doi: 10.1007/s00709-015-0796-3. . . ; : –. . doi: PubMed DOI

El-Shenawy NS, Hamza RZ Nephrotoxicity of sodium valproate and protective role of L-cysteine in rats at biochemical and histological levels J Basic Clin Physiol Pharmacol. 2016;27:497. doi: 10.1515/jbcpp-2015-0106. . . ; : –. . doi: PubMed DOI

Chaudhary S, Ganjoo P, Raiusddin S, Parvez S Nephroprotective activities of quercetin with potential relevance to oxidative stress induced by valproic acid Protoplasma. 2015;252:209. doi: 10.1007/s00709-014-0670-8. . . ; : –. . doi: PubMed DOI

Koroglu OF, Gunata M, Vardi N, Yildiz A, Ates B, Colak C, Tanriverdi LH, Parlakpinar H Protective effects of naringin on valproic acid-induced hepatotoxicity in rats Tissue Cell. 2021;72:101526. doi: 10.1016/j.tice.2021.101526. . . ; : . doi: PubMed DOI

Jutrić D, Đikić D, Boroš A, Odeh D, Drozdek SD, Gračan R, Dragičević P, Crnić I, Jurčević IL Effects of naringin and valproate interaction on liver steatosis and dyslipidaemia parameters in male C57BL6 mice Arh Hig Rada Toksikol. 2022;73:71. doi: 10.2478/aiht-2022-73-3608. . . ; : –. . doi: PubMed DOI PMC

Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J Naringin and naringenin: their mechanisms of action and the potential anticancer activities Biomedicines. 2022;10:1686. doi: 10.3390/biomedicines10071686. . . ; : . doi: PubMed DOI PMC

Amini N, Maleki M, Badavi M Nephroprotective activity of naringin against chemical-induced toxicity and renal ischemia/reperfusion injury: A review Avicenna J Phytomed. 2022;12:357. doi: 10.22038/AJP.2022.19620. . . ; : –. . doi: PubMed DOI PMC

Wang R, Wu G, Dai T, Lang Y, Chi Z, Yang S, Dong D Naringin attenuates renal interstitial fibrosis by regulating the TGF-β/Smad signaling pathway and inflammation Exp Ther Med. 2021;21:66. doi: 10.3892/etm.2020.9498. . . ; : . doi: PubMed DOI PMC

Elsawy H, Alzahrani AM, Alfwuaires M, Abdel-Moneim AM, Khalil M Nephroprotective effect of naringin in methotrexate induced renal toxicity in male rats Biomed Pharmacother. 2021;143:112180. doi: 10.1016/j.biopha.2021.112180. . . ; : . doi: PubMed DOI

Committee for the Update of the Guide for the Care and Use of Laboratory Animals . Guide for the care and use of laboratory animals. 8th ed. Washington (DC): National Academies Press; 2011. . . : ; .

Landeka Jurčević I, Dora M, Guberović I, Petras M, Rimac S, Brnčić, Đikić D Polyphenols from wine lees as a novel functional bioactive compound in the protection against oxidative stress and hyperlipidaemia Food Technol Biotechnol. 2017;55:109. doi: 10.17113/ftb.55.01.17.4894. . . ; : –. . doi: PubMed DOI PMC

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ Protein measurement with the Folin phenol reagent J Biol Chem. 1951;193:265. doi: 10.1016/S0021-9258(19)52451-6. . . ; : –. . doi: PubMed DOI

Flohé L, Ötting F Superoxide dismutase assays Meth Enzymol. 1984;105:93. doi: 10.1016/s0076-6879(84)05013-8. . . ; : –. . doi: PubMed DOI

Aebi H Catalase in vitro Meth Enzymol. 1984;105:121. doi: 10.1016/s0076-6879(84)05016-3. . . ; : –. . doi: PubMed DOI

Eyer P, Worek F, Kiderlen D, Sinko G, Stuglin A, Simeon-Rudolf V, Reiner E Molar absorption coefficients for the reduced Ellman reagent: reassessment Anal Biochem. 2003;312:224. doi: 10.1016/s0003-2697(02)00506-7. . . ; : –. . doi: PubMed DOI

Pirahanchi Y, Jessu R, Aeddula NR . Physiology, sodium potassium pump. Treasure Island (FL): StatPearls Publishing; 2022. . . . ; . PubMed

White KE, Gesek FA, Nesbitt T, Drezner MK, Friedman PA Molecular dissection of Ca2+ efflux in immortalized proximal tubule cells J Gen Physiol. 1997;109:217. doi: 10.1085/jgp.109.2.217. . . ; : –. . doi: PubMed DOI PMC

Curry JN, Yu ASL Paracellular calcium transport in the proximal tubule and the formation of kidney stones Am J Physiol Renal Physiol. 2019;316:966. doi: 10.1152/ajprenal.00519.2018. . . ; : –. . doi: PubMed DOI PMC

Gumz ML, Lynch IJ, Greenlee MM, Cain BD, Wingo CS The renal H+-K+-ATPases: physiology, regulation, and structure Am J Physiol Renal Physiol. 2010;298:12. doi: 10.1152/ajprenal.90723.2008. . . ; : –. . doi: PubMed DOI PMC

Đikić D, Jutrić D, Dominko K The dual nature of the antiepileptic drug valproic acid, with possible beneficial effects in Alzheimer’s disease SEEMEDJ. 2017;1:74. doi: 10.26332/seemedj.v1i1.26. . . ; : –. . doi: DOI

Monostory K, Nagy A, Tóth K, Bűdi T, Kiss Á, Déri M, Csukly G Relevance of CYP2C9 function in valproate therapy Curr Neuropharmacol. 2019;17:99. doi: 10.2174/1570159X15666171109143654. . . ; : –. . doi: PubMed DOI PMC

Knights KM, Rowland A, Miners JO Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) Br J Clin Pharmacol. 2013;76:587. doi: 10.1111/bcp.12086. . . ; : –. . doi: PubMed DOI PMC

Ding S, Qiu H, Huang J, Chen R, Zhang J, Huang B, Zou X, Cheng O, Jiang Q Activation of 20-HETE/PPARs involved in reno-therapeutic effect of naringenin on diabetic nephropathy Chem Biol Interact. 2019;307:116. doi: 10.1016/j.cbi.2019.05.004. . . ; : –. . doi: PubMed DOI

Oyagbemi AA, Omobowale TO, Adejumobi OA, Owolabi AM, Ogunpolu BS, Falayi OO, Hassan FO, Ogunmiluyi IO, Asenuga ER, Ola-Davies OE, Soetan KO, Saba AB, Adedapo AA, Nkadimeng SM, McGaw LJ, Oguntibeju OO, Yakubu MA Antihypertensive power of Naringenin is mediated via attenuation of mineralocorticoid receptor (MCR)/angiotensin converting enzyme (ACE)/kidney injury molecule (Kim-1) signaling pathway Eur J Pharmacol. 2020;880:173142. doi: 10.1016/j.ejphar.2020.173142. . . ; : . doi: PubMed DOI

Amudha K, Pari L Beneficial role of naringin, a flavanoid on nickel induced nephrotoxicity in rats Chem Biol Interact. 2011;193:57. doi: 10.1016/j.cbi.2011.05.003. . . ; : –. . doi: PubMed DOI

Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage Environ Sci Pollut Res Int. 2018;25:20968. doi: 10.1007/s11356-018-2242-5. . . ; : –. . doi: PubMed DOI

Singh D, Chander V, Chopra K Protective effect of naringin, a bioflavonoid on glycerol-induced acute renal failure in rat kidney Toxicology. 2004;201:143. doi: 10.1016/j.tox.2004.04.018. . . ; : –. . doi: PubMed DOI

Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A, Badavi M The renoprotective effects of naringin and trimetazidine on renal ischemia/reperfusion injury in rats through inhibition of apoptosis and downregulation of micoRNA-10a Biomed Pharmacother. 2019;112:108568. doi: 10.1016/j.biopha.2019.01.029. . . ; : . doi: PubMed DOI

Galati G, Chan T, Wu B, O’Brien PJ Glutathione-dependent generation of reactive oxygen species by the peroxidase-catalyzed redoxcycling of flavonoids Chem Res Toxicol. 1999;12:521. doi: 10.1021/tx980271b. . . ; : –. . doi: PubMed DOI