Abstract
Background
Renal interstitial fibrosis is the common pathway in progressive renal diseases, where oxidative stress promotes inflammation and macrophage infiltration. Febuxostat is a novel nonpurine xanthine oxidase (XO)-specific inhibitor for treating hyperuricemia. While some reports suggest a relationship between hyperuricemia and chronic kidney disease (CKD), the renoprotective mechanism of an XO inhibitor in CKD remains unknown. Recent reports have focused on XO as a source of oxidative stress.
Methods
Here, we investigate the potential of febuxostat to reduce fibrogenic and inflammatory responses in an established interstitial fibrosis model—unilateral ureteric obstruction (UUO). Male Sprague–Dawley rats were divided into three groups: sham-operated group, vehicle-treated UUO group, and febuxostat-treated UUO group.
Results
Treatment with febuxostat diminished XO activity in obstructed kidneys, and suppressed nitrotyrosine, a marker of oxidative stress. Consequently, febuxostat inhibited early proinflammatory cytokine expression, followed by a reduction of interstitial macrophage infiltration. In addition, febuxostat suppressed transforming growth factor-β messenger RNA expression, thereby ameliorating smooth muscle alpha actin and type I collagen expression.
Conclusion
Our results provide evidence for the renoprotective action of febuxostat against the formation of interstitial fibrosis. A decrease in macrophage infiltration and interstitial fibrosis, along with a decrease of the oxidative stress marker, strongly suggests the existence of a causal relationship between them. Febuxostat may have therapeutic value in slowing or preventing interstitial fibrosis in patients with CKD.
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References
Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, Collins AJ, Levey AS, Menon V. Uric acid and long-term outcomes in CKD. Am J Kidney Dis. 2009;53:796–803.
Suliman ME, Johnson RJ, Garcia-Lopez E, Qureshi AR, Molinaei H, Carrero JJ, Heimburger O, Barany P, Axelsson J, Lindholm B, Stenvinkel P. J-shaped mortality relationship for uric acid in CKD. Am J Kidney Dis. 2006;48:761–71.
Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincon A, Arroyo D, Luno J. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–93.
Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Wessale JL, Zhao L, Johnson RJ. Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia. Nephron Physiol. 2008;108:69–78.
Kosugi T, Nakayama T, Heinig M, Zhang L, Yuzawa Y, Sanchez-Lozada LG, Roncal C, Johnson RJ, Nakagawa T. Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice. Am J Physiol Renal Physiol. 2009;297:F481–8.
Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens. 2008;26:269–75.
Kawada N, Moriyama T, Ando A, Fukunaga M, Miyata T, Kurokawa K, Imai E, Hori M. Increased oxidative stress in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 1999;56:1004–13.
Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010;28:1234–42.
McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985;312:159–63.
Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007;293:C584–96.
Landmesser U, Spiekermann S, Preuss C, Sorrentino S, Fischer D, Manes C, Mueller M, Drexler H. Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol. 2007;27:943–8.
Young MR, Young IS, Johnston SR, Rowlands BJ. Lipid peroxidation assessment of free radical production following release of obstructive uropathy. J Urol. 1996;156:1828–32.
Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S, Becker MA. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005;76:1835–47.
Horiuchi H, Ota M, Kobayashi M, Kaneko H, Kasahara Y, Nishimura S, Kondo S, Komoriya K. A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. Res Commun Mol Pathol Pharmacol. 1999;104:307–19.
Beckman JS, Parks DA, Pearson JD, Marshall PA, Freeman BA. A sensitive fluorometric assay for measuring xanthine dehydrogenase and oxidase in tissues. Free Radic Biol Med. 1989;6:607–15.
Mohiuddin I, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Nitrotyrosine and chlorotyrosine: clinical significance and biological functions in the vascular system. J Surg Res. 2006;133:143–9.
Greene EL, Paller MS. Xanthine oxidase produces O −.2 in posthypoxic injury of renal epithelial cells. Am J Physiol. 1992;263:F251–5.
Contrin LM, Lobo SM, Navegantes LC, Orrico SP, Queiroz MM, Cury PM, Lira EC, Carta A, Yamamoto AE, Vincent JL. Tyrosine: a possible marker of severe intestinal injury during ischemia. J Surg Res. 2009;155:268–72.
Paul-Clark MJ, McMaster SK, Sorrentino R, Sriskandan S, Bailey LK, Moreno L, Ryffel B, Quesniaux VF, Mitchell JA. Toll-like receptor 2 is essential for the sensing of oxidants during inflammation. Am J Respir Crit Care Med. 2009;179:299–306.
Moriyama T, Kawada N, Akagi Y, Ando A, Horio M, Yamauchi A, Nagata K, Imai E, Hori M. TCV-116 inhibits interstitial fibrosis and HSP47 mRNA in rat obstructive nephropathy. Kidney Int Suppl. 1997;63:S232–5.
Bascands JL, Schanstra JP. Obstructive nephropathy: insights from genetically engineered animals. Kidney Int. 2005;68:925–37.
Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, Kinugawa T, Igawa O, Hisatome I, Shigemasa C, Anker SD, Doehner W. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail. 2010;3:73–81.
Aslam S, Santha T, Leone A, Wilcox C. Effects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis. Kidney Int. 2006;70:2109–15.
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Omori, H., Kawada, N., Inoue, K. et al. Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy. Clin Exp Nephrol 16, 549–556 (2012). https://doi.org/10.1007/s10157-012-0609-3
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DOI: https://doi.org/10.1007/s10157-012-0609-3