Background/Aims: The effect of febuxostat (Fx), a non-purine and selective xanthine oxidase inhibitor, on glomerular microcirculatory changes in 5/6 nephrectomy (5/6 Nx) Wistar rats with and without oxonic acid (OA)-induced hyperuricemia was evaluated. Methods: Four groups were studied: 5/6 Nx+vehicle (V)+placebo (P) (n = 7); 5/6 Nx+V+Fx (n = 8); 5/6 Nx+OA+P (n = 6) and 5/6 Nx+OA+Fx (n = 10). OA (750 mg/kg/day, oral gavage) and Fx (3–4 mg/kg/day, drinking water) were administered for 4 weeks. Systolic blood pressure, proteinuria and plasma uric acid were measured at baseline and at the end of 4 weeks. Measurement of glomerular hemodynamics and evaluation of histology were performed at the end of 4 weeks. Results: 5/6 Nx+OA+P rats developed hyperuricemia, renal vasoconstriction and glomerular hypertension in association with further aggravation of afferent arteriolopathy compared to 5/6 Nx+V+P. Fx prevented hyperuricemia in 5/6 Nx+OA+Fx rats and ameliorated proteinuria, preserved renal function and prevented glomerular hypertension in both 5/6 Nx+V+Fx and 5/6 Nx+OA+Fx groups. Functional improvement was accompanied by preservation of afferent arteriolar morphology and reduced tubulointerstitial fibrosis. Conclusion: Fx prevented renal injury in 5/6 Nx rats with and without coexisting hyperuricemia. Because Fx helped to preserve preglomerular vessel morphology, normal glomerular pressure was maintained even in the presence of systemic hypertension.

Keywords:
Chronic renal damage, Glomerular hypertension, Hyperuricemia, Febuxostat, Arteriolopathy, Micropuncture
1.
Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH: Hyperuricemia in primary and renal hypertension. N Engl J Med 1966;275:457–464.
2.
McBride MB, Rigden S, Haycock GB, Dalton N, Van’t HW, Rees L, Raman GV, Moro F, Ogg CS, Cameron JS, Simmonds HA: Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children. Pediatr Nephrol 1998;12:357–364.
3.
Johnson RJ, Feig DI, Herrera-Acosta J, Kang DH: Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 2005;45:18–20.
4.
Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S: Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004;44:642–650.
5.
Alderman MH, Cohen H, Madhavan S, Kivlighn S: Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999;34:144–150.
6.
Lee JE, Kim YG, Choi YH, Huh W, Kim DJ, Oh HY: Serum uric acid is associated with microalbuminuria in prehypertension. Hypertension 2006;47:962–967.
7.
Syamala S, Li J, Shankar A: Association between serum uric acid and prehypertension among US adults. J Hypertens 2007;25:1583–1589.
8.
Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG: Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med 1980;93:817–821.
9.
Siu YP, Leung KT, Tong MK, Kwan TH: Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51–59.
10.
Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76:47–56.
11.
Kanbay M, Ozkara A, Selcoki Y, Isik B, Turgut F, Bavbek N, Uz E, Akcay A, Yigitoglu R, Covic A: Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearance, and proteinuria in patients with normal renal functions. Int Urol Nephrol 2007;39:1227–1233.
12.
Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101–1106.
13.
Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, Kang DH, Gordon KL, Watanabe S, Nakagawa T, Lan HY, Johnson RJ: Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-F997.
14.
Mazzali M, Kim YG, Suga S, Gordon KL, Kang DH, Jefferson JA, Hughes J, Kivlighn SD, Lan HY, Johnson RJ: Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation 2001;71:900–905.
15.
Sanchez-Lozada LG, Tapia E, vila-Casado C, Soto V, Franco M, Santamaria J, Nakagawa T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J: Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 2002;283:F1105-F1110.
16.
Sanchez-Lozada LG, Tapia E, Santamaria J, Avila-Casado C, Soto V, Nepomuceno T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J: Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int 2005;67:237–247.
17.
Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450–2461.
18.
Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, Vernillet L, Joseph-Ridge N: Febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: a 28-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 2005;52:916–923.
19.
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;76:1835–1847.
20.
Osada Y, Tsuchimoto M, Fukushima H, Takahashi K, Kondo S, Hasegawa M, Komoriya K: Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents. Eur J Pharmacol 1993;241:183–188.
21.
Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T: An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem 2003;278:1848–1855.
22.
Henry RJ, Sobel Ch, Segalove M: Turbidimetric determination of proteins with sulfosalicylic and trichloroacetic acids. Proc Soc Exp Biol Med 1956;92:748–751.
23.
Davidson WD, Sackner MA: Simplification of the anthrone method for the determination of inulin in clearance studies. J Lab Clin Med 1963;62:351–356.
24.
Vurek G, Pegram S: Fluorometric method for the determination of nanogram quantities of inulin. Ann Biochem 1966;16:409–419.
25.
Viets JW, Deen WM, Troy JL, Brenner BM: Determination of serum protein concentration in nanoliter blood samples using fluorescamine or 9-phthalaldehyde. Anal Biochem 1978;88:513–521.
26.
Baylis C, Deen WM, Myers BD, Brenner BM: Effects of some vasodilator drugs on transcapillary fluid exchange in renal cortex. Am J Physiol 1976;230:1148–1158.
27.
Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ: A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13:2888–2897.
28.
Brenner BM: Nephron adaptation to renal injury or ablation. Am J Physiol 1985;249:F324-F337.
29.
Pelayo JC, Shanley PF: Glomerular and tubular adaptive responses to acute nephron loss in the rat. Effect of prostaglandin synthesis inhibition. J Clin Invest 1990;85:1761–1769.
30.
Sanchez-Lozada LG, Tapia E, Johnson RJ, Rodriguez-Iturbe B, Herrera-Acosta J: Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation. Kidney Int Suppl 2003;S9–S14.
31.
Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Zhao L, Johnson RJ: Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricemia. Nephrol Dial Transplant 2008;23:1179–1185.
32.
Kretschmer BD, Schelling P, Beier N, Liebscher C, Treutel S, Kruger N, Scholz HP, Haus A: Modulatory role of food, feeding regime and physical exercise on body weight and insulin resistance. Life Sci 2005;76:1553–1573.
33.
Hayslett JP: Functional adaptation to reduction in renal mass. Physiol Rev 1979;59:137–164.
34.
Gilbert RM, Weber H, Turchin L, Fine LG, Bourgoignie JJ, Bricker NS: A study of the intrarenal recycling of urea in the rat with chronic experimental pyelonephritis. J Clin Invest 1976;58:1348–1357.
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2008
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