Effect of Febuxostat on the Progression of Renal Disease in 5/6 Nephrectomy Rats with and without Hyperuricemia

Sánchez‐Lozada, Laura G.; Tapia, Edilia; Soto, Virgilia; Ávila-Casado, Carmen; Franco, Martha; Wessale, Jerry L.; Zhao, Lin; Johnson, Richard J.

doi:10.1159/000127837

Cited by 98 publications

(80 citation statements)

References 62 publications

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“…Therefore, because febuxostat inhibits both oxidized and reduced forms of XO, it can also inhibit ROS formation and inflammation induced by oxidative stress [12]. The renoprotective effects of XO inhibitors have been demonstrated in experimental animal models, including 5/6 nephrectomized rats [13], renal ischemic-reperfusion injury rats [14], unilateral-ureteral obstruction rats [15], and fructose-induced metabolic syndrome rats [16,17]. However, few studies have investigated the anti-inflammatory and antioxidative effects of febuxostat in early DN.…”

Section: Introductionmentioning

confidence: 99%

Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model

Lee

Jeong²,

Kim³

et al. 2014

Am J Nephrol

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Background: Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. Methods: Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. Results: Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. Conclusions: Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities.

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Section: Introductionmentioning

confidence: 99%

Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model

Lee

Jeong²,

Kim³

et al. 2014

Am J Nephrol

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“…Functional improvement was accompanied by preservation of afferent arteriolar morphology and reduced tubulointerstitial fi brosis. These results suggested that febuxostat prevented renal injury in 5/6 Nx rats with and without coexisting hyperuricemia and due to its effect on preserving preglomerular vessel morphology, normal glomerular pressure was maintained even in the presence of systemic hypertension (Sanchez-Lozada et al 2008b).…”

Section: Pharmacologymentioning

confidence: 75%

“…Considering the close association between prolonged hyperuricemia and renal disease, Sanchez-Lozada et al evaluated the effect of febuxostat on progressive renal disease in a 5/6 nephrectomy (5/6 Nx) model in Wistar rats with and without hyperuricemia induced by the uricase inhibitor oxonic acid (OA) (Sanchez-Lozada et al 2008b). The 5/6 Nx rats given OA and placebo developed hyperuricemia, renal vasoconstriction and glomerular hypertension in association with further aggravation of afferent arteriolopathy compared with those without OA-induced hyperuricemia.…”

Section: Pharmacologymentioning

confidence: 99%

Febuxostat in the management of hyperuricemia and chronic gout: a review

Tomlinson

2008

TCRM

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Abstract:Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insuffi ciency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout fl ares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the fi rst major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and effi cacy is required.

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“…It is well known that Fx is effective in preventing renal injury in animal models of diabetic nephropathy and 5/6 nephrectomy rats [11,12]. In this study, we tested whether the protective effect of Fx also extends to Tac-induced renal injury.…”

Section: Discussionmentioning

confidence: 98%

“…Febuxostat (Fx), a non-purine selective inhibitor of xanthine oxidase (XO), is a new uric acid-lowering agent that is different from allopurinol in that it does not inhibit other enzymes in the purine and pyrimidine metabolism pathways, and thus produces fewer reactive oxygen species (ROS) [9], and has fewer side effects than does allopurinol [10]. In addition, a recent publication showed that Fx is effective in preventing renal injury in an animal model of diabetic nephropathy and in 5/6 nephrectomy rats [11,12]. …”

Section: Introductionmentioning

confidence: 99%

The Protective Effect of Febuxostat on Chronic Tacrolimus-Induced Nephrotoxicity in Rats

Kim¹,

Lim²,

Jin³

et al. 2016

Nephron

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Background: The use of calcineurin inhibitors is a well-known risk factor for hyperuricemia in kidney transplant recipients. We evaluated the effect of febuxostat (Fx), a new uric acid-lowering drug, on hyperuricemia and renal injury in an experimental model of chronic tacrolimus (Tac)-induced nephropathy. Methods: Chronic Tac nephropathy was induced by administering Tac (1.5 mg/kg/day) to rats on a low-salt diet (0.05%) with oxonic acid (OA, 2%, 0.2 g/kg/day) for 28 days. Two doses of Fx (5 and 10 mg/kg) were concomitantly administered with Tac or vehicle (Vh). We evaluated the effect of Fx on hyperuricemia by measuring serum uric acid (SUA) levels, fractional excretion of uric acid (FEUA), and urate transporters in Tac-induced nephropathy. The effects of Fx on Tac-induced renal injury were evaluated in terms of renal function and arteriolopathy, tubulointerstitial fibrosis, inflammation, and apoptosis. We evaluated oxidative stress as a protective mechanism via xanthine oxidase (XO) activity, and as a marker of oxidative stress (via evaluation of levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-hexenal (4-HHE)). Results: The Tac group showed higher SUA levels and lower FEUA than did the Vh group, but Fx treatment significantly decreased SUA levels in a dose-dependent manner, with an increase of FEUA at a high dose (10 mg/kg). Tac treatment increased urate-anion exchanger 1 and decreased organic anion transporter type 1 expression in renal tubular cells, but Fx treatment reversed the effects on those transporters. Impaired renal function and histological injury (interstitial fibrosis, inflammation, and arteriolopathy) in the Tac group were markedly improved by Fx administration. Increases in apoptotic cell death and activation of proapoptotic caspase-3 by Tac were remarkably decreased by Fx treatment. Tac administration increased the activity of XO in kidney tissue and serum, and the levels of 8-OHdG in urine and 8-OHdG and 4-HHE of kidney tissue, but combined treatment with Fx decreased the levels of these parameters. Conclusions: Fx is effective in controlling hyperuricemia and in preventing Tac-induced renal injury, via a reduction of oxidative stress. Therefore, a targeted therapy aimed at inhibiting uric acid by Fx may be a useful approach in the management of the progression of nephropathy in renal transplant patients treated with Tac.

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Effect of Febuxostat on the Progression of Renal Disease in 5/6 Nephrectomy Rats with and without Hyperuricemia

Cited by 98 publications

References 62 publications

Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model

Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model

Febuxostat in the management of hyperuricemia and chronic gout: a review

The Protective Effect of Febuxostat on Chronic Tacrolimus-Induced Nephrotoxicity in Rats

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