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

Lee, Hong-Joo; Jeong, Kyung Hwan; Kim, Yang‐Gyun; Moon, Joo Young; Lee, Sang Ho; Ihm, Chun Gyoo; Sung, Ji Youn; Lee, Tae Won

doi:10.1159/000363421

Cited by 59 publications

(47 citation statements)

References 31 publications

(35 reference statements)

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“…Many inflammationrelated proteins regulated by NF-κB, such as vascular cell adhesion protein 1, intercellular adhesion molecule 1 and monocyte chemotactic protein 1, play important roles in kidney diseases (65)(66)(67)(68)(69). Many stimuli relevant to kidney injury can activate NF-κB, such as high glucose, advanced glycosylation end products, cytokines, growth factors, toll-like receptors and proteinuria.…”

Section: Sirt1 Suppresses Inflammation By Targeting Nf-κb and High-momentioning

confidence: 99%

Sirtuin 1: A Target for Kidney Diseases

Kong

Zhou

et al. 2015

Mol Med

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Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD + -dependent histone deacetylase that is necessary for caloric restriction-related lifespan extension. SIRT1, as an intracellular energy sensor, detects the concentration of intracellular NAD + and uses this information to adapt cellular energy output to cellular energy requirements. Previous studies on SIRT1 have confirmed its beneficial effects on cellular immunity to oxidative stress, reduction of fibrosis, suppression of inflammation, inhibition of apoptosis, regulation of metabolism, induction of autophagy and regulation of blood pressure. All of the above biological processes are involved in the pathogenesis of kidney diseases. Therefore, the activation of SIRT1 may become a therapeutic target to improve the clinical outcome of kidney diseases. In this review, we give an overview of SIRT1 and its molecular targets as well as SIRT1-modulated biological processes, with a particular focus on the role of SIRT1 in kidney diseases.

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Section: Sirt1 Suppresses Inflammation By Targeting Nf-κb and High-momentioning

confidence: 99%

Sirtuin 1: A Target for Kidney Diseases

Kong

Zhou

et al. 2015

Mol Med

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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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“…These effects were comparable for both drugs. Recently, several studies reported that allopurinol reduced tubulointerstitial injury in db/db mice [10], and febuxostat and topiroxostat ameliorated nitro-oxidative stress and inflammation in streptozotocin (STZ)-induced diabetic rats [11] and in adenineinduced renal injury mouse [12], respectively. These previous results suggest that the XOR inhibitors, topiroxostat, febuxostat, and allopurinol, might contribute to UAE reduction and renoprotection by moderating renal oxidative stress and inflammation via suppression of XOR-induced superoxide production.…”

Section: Discussionmentioning

confidence: 99%

“…tubulointerstitial injury by lowering UA [10] and febuxostat and topiroxostat had a renoprotective effect by attenuating inflammatory and oxidative stress in an animal model of diabetes [11] and of adenine-induced renal injury [12], respectively. Compared with that reported for placebo, topiroxostat has been shown to decrease the urinary albuminto-creatinine ratio (ACR) in patients with chronic kidney disease (stage 3) with hyperuricemia in clinical trial [13] and an animal model of diabetic nephropathy [14].…”

Section: Introductionmentioning

confidence: 99%