Short-term fructose exposure may perturb the nitric oxide (NO)/reactive oxygen species (ROS) balance before hemodynamic changes development. Male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) rats received 10 % fructose in drinking water for 3 weeks or remained on tap water. We assessed systolic blood pressure (tail-cuff), plasma lipid levels, tissue conjugated diene concentrations, protein expression of NADPH oxidase, NF-kappaB, and SOD (Western blot), and total NO synthase (NOS) activity ([3H]-L-arginine to [3H]-L-citrulline). Fructose did not change blood pressure in either strain, but increased kidney-to-body-weight ratio in SHR. In WKY, plasma HDL level decreased; in SHR, total cholesterol, VLDL, and triglycerides increased. Conjugated diene concentration increased in the kidney of WKY but not in the heart. Fructose upregulated renal NADPH oxidase and downregulated renal SOD in SHR, with no change in cardiac NADPH oxidase. NF-?B protein expression did not change in either tissue. NOS activity decreased in the heart and kidney of WKY and in the kidney of SHR. We can conclude that even moderate, short-term fructose intake induces strain-dependent dyslipidemia and an early shift of the renal redox milieu toward oxidative stress, accompanied by reduced NOS activity, while leaving blood pressure unchanged. The kidney appears more susceptible than the heart, particularly in the hypertensive background, highlighting the NO/ROS axis as an early target for intervention.

Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Bratislava Slovak Republic

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De Koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 2012;125:1735–1741. doi: 10.1161/CIRCULATIONAHA.111.067017. PubMed DOI PMC

Li B, Yan N, Jiang H, Cui M, Wu M, Wang L, Mi B, Li Z, Shi J, Fan Y, Azalati MM, Li C, Chen F, Ma M, Wang D, Ma L. Consumption of sugar sweetened beverages, artificially sweetened beverages and fruit juices and risk of type 2 diabetes, hypertension, cardiovascular disease, and mortality: A meta-analysis. Front Nutr. 2023;10:1019534. doi: 10.3389/fnut.2023.1019534. PubMed DOI PMC

Bray GA. Fructose and risk of cardiometabolic disease. Curr Atheroscler Rep. 2012;14:570–578. doi: 10.1007/s11883-012-0276-6. PubMed DOI PMC

Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch. 2020;472:1207–1248. https://doi.org/10.1007/s00424-020-02439-5, https://doi.org/10.1007/s00424-020-02441-x, https://doi.org/10.1007/s00424-020-02442-w. PubMed DOI PMC

Jang C, Wada S, Yang S, Gosis B, Zeng X, Zhang Z, Shen Y, Lee G, Arany Z, Rabinowitz JD. The small intestine shields the liver from fructose-induced steatosis. Nat Metab. 2020;2:586–593. doi: 10.1038/s42255-020-0222-9. PubMed DOI PMC

Geidl-Flueck B, Gerber PA. Fructose drives de novo lipogenesis affecting metabolic health. J Endocrinol. 2023;257:e220270. doi: 10.1530/JOE-22-0270. PubMed DOI PMC

Vieira FO, Leal VDEO, Stockler-Pinto MB, Barros ADEF, Borges NA, Lobo JC, Mafra D. Fructose intake: Is there an association with uric acid levels in nondialysis-dependent chronic kidney disease patients? Nutr Hosp. 2014;31:772–777. doi: 10.3305/nh.2015.31.2.7796. PubMed DOI

Lubawy M, Formanowicz D. High-fructose diet-induced hyperuricemia accompanying metabolic syndrome-mechanisms and dietary therapy proposals. Int J Environ Res Public Health. 2023;20:3596. doi: 10.3390/ijerph20043596. PubMed DOI PMC

Gersch C, Palii SP, Kim KM, Angerhofer A, Johnson RJ, Henderson GN. Inactivation of nitric oxide by uric acid. Nucleosides Nucleotides Nucleic Acids. 2008;27:967–978. doi: 10.1080/15257770802257952. PubMed DOI PMC

Warren BE, Lou PH, Lucchinetti E, Zhang L, Clanachan AS, Affolter A, Hersberger M, Zaugg M, Lemieux H. Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat. Am J Physiol Endocrinol Metab. 2014;306(6):E658–67. doi: 10.1152/ajpendo.00511.2013. Erratum in: Am J Physiol Endocrinol Metab 2014; 307:E1166. PubMed DOI PMC

Crescenzo R, Bianco F, Coppola P, Mazzoli A, Cigliano L, Liverini G, Iossa S. Increased skeletal muscle mitochondrial efficiency in rats with fructose-induced alteration in glucose tolerance. Br J Nutr. 2013;110:1996–2003. doi: 10.1017/S0007114513001566. PubMed DOI

Giacchetti G, Sechi LA, Griffin CA, Don BR, Mantero F, Schambelan M. The tissue renin-angiotensin system in rats with fructose-induced hypertension: overexpression of type 1 angiotensin II receptor in adipose tissue. J Hypertens. 2000;18:695–702. doi: 10.1097/00004872-200018060-00006. PubMed DOI

Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–1148. doi: 10.1161/01.RES.74.6.1141. PubMed DOI

Sachse A, Wolf G. Angiotensin II-induced reactive oxygen species and the kidney. J Am Soc Nephrol. 2007;18:2439–2446. doi: 10.1681/ASN.2007020149. PubMed DOI

Liu H, Colavitti R, Rovira II, Finkel T. Redox-dependent transcriptional regulation. Circ Res. 2005;97:967–974. doi: 10.1161/01.RES.0000188210.72062.10. PubMed DOI

Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kB Signaling. Cell Res. 2011;21:103–115. doi: 10.1038/cr.2010.178. PubMed DOI PMC

Quilley J. Oxidative Stress and inflammation in the endothelial dysfunction of obesity: A role for NFkB? J Hypertens. 2011;2010;28:2010–2011. doi: 10.1097/HJH.0b013e32833e24cb. PubMed DOI PMC

Nakagawa T, Johnson RJ, Andres-Hernando A, Roncal-Jimenez C, Sanchez-Lozada LG, Tolan DR, Lanaspa MA. Fructose production and metabolism in the kidney. J Am Soc Nephrol. 2020;31:898–906. doi: 10.1681/ASN.2019101015. PubMed DOI PMC

Scurt FG, Ganz MJ, Herzog C, Bose K, Mertens PR, Chatzikyrkou C. Association of metabolic syndrome and chronic kidney disease. Obes Rev. 2024;25(1):e13649. doi: 10.1111/obr.13649. PubMed DOI

Cebova M, Klimentova J, Janega P, Pechanova O. Effect of bioactive compound of Aronia melanocarpa on cardiovascular system in experimental hypertension. Oxid Med Cell Longev. 2017;2017:8156594. doi: 10.1155/2017/8156594. PubMed DOI PMC

Pechanova O, Barta A, Koneracka M, Zavisova V, Kubovcikova M, Klimentova J, Török J, Zemancikova A, Cebova M. Protective effects of nanoparticle-loaded aliskiren on cardiovascular system in spontaneously hypertensive rats. Molecules. 2019;24:2710. doi: 10.3390/molecules24152710. PubMed DOI PMC

Şaman E, Cebova M, Barta A, Koneracka M, Zavisova V, Eckstein-Andicsova A, Danko M, Mosnacek J, Pechanova O. Combined therapy with simvastatin- and Coenzyme-Q10-loaded nanoparticles upregulates the Akt-eNOS pathway in experimental metabolic syndrome. Int J Mol Sci. 2022;24:276. doi: 10.3390/ijms24010276. PubMed DOI PMC

La Russa D, Brunelli E, Pellegrino D. Oxidative imbalance and kidney damage in spontaneously hypertensive rats: activation of extrinsic apoptotic pathways. Clin Sci (Lond) 2017;131:1419–1428. doi: 10.1042/CS20170177. PubMed DOI

Dovinova I, Kvandova M, Balis P, Gresova L, Majzunova M, Horakova L, Chan JY, Barancik M. The role of Nrf2 and PPARgamma in the improvement of oxidative stress in hypertension and cardiovascular diseases. Physiol Res. 2020;69(Suppl 4):S541–S553. doi: 10.33549/physiolres.934612. PubMed DOI PMC

Vokurková M, Rauchová H, Řezáčová L, Vaněčková I, Zicha J. ROS production is increased in the kidney but not in the brain of Dahl rats with salt hypertension elicited in adulthood. Physiol Res. 2015;64:303–312. doi: 10.33549/physiolres.933054. PubMed DOI

Kojšová S, Jendeková L, Zicha J, Kuneš J, Andriantsitohaina R, Pecháňová O. the effect of different antioxidants on nitric oxide production in hypertensive rats. Physiol Res. 2006;55(Suppl 1):S3–S16. doi: 10.33549/physiolres.930000.55.S1.3. PubMed DOI

D'Angelo G, Elmarakby AA, Pollock DM, Stepp DW. Fructose feeding increases insulin resistance but not blood pressure in Sprague-Dawley rats. Hypertension. 2005;46:806–811. doi: 10.1161/01.HYP.0000182697.39687.34. PubMed DOI

Sánchez-Lozada LG, Tapia E, Jiménez A, Bautista P, Cristóbal M, Nepomuceno T. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats. Am J Physiol Renal Physiol. 2007;292:F423–F429. doi: 10.1152/ajprenal.00124.2006. PubMed DOI

Zemančíková A, Török J. Effect of perivascular adipose tissue on arterial adrenergic contractions in normotensive and hypertensive rats with high fructose intake. Physiol Res. 2017;66(Suppl 4):S537–S544. doi: 10.33549/physiolres.933798. PubMed DOI

Johnson RJ, Sanchez-Lozada LG, Nakagawa T. The effect of fructose on renal biology and disease. J Am Soc Nephrol. 2010;21:2036–2039. doi: 10.1681/ASN.2010050506. PubMed DOI

Nakayama T, Kosugi T, Gersch M, Connor T, Sanchez-Lozada LG, Lanaspa MA, Roncal C, Perez-Pozo SE, Johnson RJ, Nakagawa T. Dietary fructose causes tubulointerstitial injury in the normal rat kidney. Am J Physiol Renal Physiol. 2010;298:F712–F720. doi: 10.1152/ajprenal.00433.2009. PubMed DOI PMC

Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increase visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–1334. doi: 10.1172/JCI37385. PubMed DOI PMC

Mikulíková K, Eckhardt A, Kunes J, Zicha J, Mikšík I. Advanced glycation end-product pentosidine accumulates in various tissues of rats with high fructose intake. Physiol Res. 2008;57:89–94. doi: 10.33549/physiolres.931093. PubMed DOI

Geidl-Flueck B, Hochuli M, Németh Á, Eberl A, Derron N, Köfeler HC, Tappy L, et al. Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial. J Hepatol. 2021;75:46–54. doi: 10.1016/j.jhep.2021.02.027. PubMed DOI

Ichigo Y, Takeshita A, Hibino M, Nakagawa T, Hayakawa T, Patel D, Field CJ, Shimada M. High-fructose diet-induced hypertriglyceridemia is associated with enhanced hepatic expression of ACAT2 in rats. Physiol Res. 2019;68:1021–1026. doi: 10.33549/physiolres.934226. PubMed DOI

Yang Q, Wu FR, Wang JN, Gao L, Jiang L, Li HD, Ma Q, et al. Nox4 in renal diseases: An update. Free Radic Biol Med. 2018;124:466–472. doi: 10.1016/j.freeradbiomed.2018.06.042. PubMed DOI

Shi X, Qiu H. New insights into energy substrate utilization and metabolic remodeling in cardiac physiological adaption. Front Physiol. 2022;13:831829. doi: 10.3389/fphys.2022.831829. PubMed DOI PMC

Sasváriová M, Salvaras L, Sečkárová Micháliková D, Tyukos Kaprinay B, Knezl V, Gáspárová Z, Stankovičová T. Assessment of the cardiovascular risk of high-fat-high-fructose diet in hereditary hypertriacylglycerolemic rats and venlafaxine effect. Physiol Res. 2024;73:973–984. doi: 10.33549/physiolres.935420. PubMed DOI PMC

Miatello R, Risler N, Castro C, González S, Rüttler M, Cruzado M. Aortic smooth muscle cell proliferation and endothelial nitric oxide synthase activity in fructose-fed rats. Am J Hypertens. 2001;14:1135–1141. doi: 10.1016/S0895-7061(01)02206-3. PubMed DOI

Palanisamy N, Venkataraman AC. beneficial effect of genistein on lowering blood pressure and kidney toxicity in fructose-fed hypertensive rats. Br J Nutr. 2013;109:1806–1812. doi: 10.1017/S0007114512003819. PubMed DOI

Okamura T, Tawa M, Geddawy A, Shimosato T, Iwasaki H, Shintaku H, Yoshida Y, Masada M, Shinozaki K, Imamura T. Effects of atorvastatin, amlodipine, and their combination on vascular dysfunction in insulin-resistant rats. J Pharmacol Sci. 2014;124:76–85. doi: 10.1254/jphs.13178FP. PubMed DOI