BACKGROUND AND PURPOSE: Elevated serum uric acid (UA) is a risk factor for the development of kidney disease. Inhibitors of xanthine oxidase (XOi), an enzyme involved in UA synthesis, have protective effects at early stages of experimental diabetic nephropathy (DN). However, long-term effects of XOi in models of DN remain to be determined. EXPERIMENTAL APPROACH: The development of albuminuria, renal structure and molecular markers of DN were studied in type 2 diabetic Zucker obese (ZO) rats treated for 18 weeks with the XOi febuxostat and compared with vehicle-treated ZO rats, ZO rats treated with enalapril or a combination of both agents, and lean Zucker rats without metabolic defects. RESULTS: Febuxostat normalized serum UA and attenuated the development of albuminuria, renal structural changes, with no significant effects on BP, metabolic control or systemic markers of oxidative stress (OS). Most of these actions were comparable with those of enalapril. Combination treatment induced marked decreases in BP and was more effective in ameliorating structural changes, expression of profibrotic genes and systemic OS than either monotherapy. Febuxostat attenuated renal protein expression of TGF-ß, CTGF, collagen 4, mesenchymal markers (FSP1 and vimentin) and a tissue marker of OS nitrotyrosine. Moreover, febuxostat attenuated TGF-ß- and S100B-induced increased expression of fibrogenic molecules in renal tubular cells in vitro in UA-free media in an Akt kinase-dependent manner. CONCLUSIONS AND IMPLICATIONS: Febuxostat is protective and enhances the actions of enalapril in experimental DN. Multiple mechanisms might be involved, such as a reduction of UA, renal OS and inhibition of profibrotic signalling.
BACKGROUND AND PURPOSE: Elevated serum uric acid (UA) is a risk factor for the development of kidney disease. Inhibitors of xanthine oxidase (XOi), an enzyme involved in UA synthesis, have protective effects at early stages of experimental diabetic nephropathy (DN). However, long-term effects of XOi in models of DN remain to be determined. EXPERIMENTAL APPROACH: The development of albuminuria, renal structure and molecular markers of DN were studied in type 2 diabetic Zucker obese (ZO) rats treated for 18 weeks with the XOi febuxostat and compared with vehicle-treated ZO rats, ZO rats treated with enalapril or a combination of both agents, and lean Zucker rats without metabolic defects. RESULTS:Febuxostat normalized serum UA and attenuated the development of albuminuria, renal structural changes, with no significant effects on BP, metabolic control or systemic markers of oxidative stress (OS). Most of these actions were comparable with those of enalapril. Combination treatment induced marked decreases in BP and was more effective in ameliorating structural changes, expression of profibrotic genes and systemic OS than either monotherapy. Febuxostat attenuated renal protein expression of TGF-ß, CTGF, collagen 4, mesenchymal markers (FSP1 and vimentin) and a tissue marker of OS nitrotyrosine. Moreover, febuxostat attenuated TGF-ß- and S100B-induced increased expression of fibrogenic molecules in renal tubular cells in vitro in UA-free media in an Akt kinase-dependent manner. CONCLUSIONS AND IMPLICATIONS: Febuxostat is protective and enhances the actions of enalapril in experimental DN. Multiple mechanisms might be involved, such as a reduction of UA, renal OS and inhibition of profibrotic signalling.
Authors: Marian Goicoechea; Soledad García de Vinuesa; Ursula Verdalles; Caridad Ruiz-Caro; Jara Ampuero; Abraham Rincón; David Arroyo; José Luño Journal: Clin J Am Soc Nephrol Date: 2010-06-10 Impact factor: 8.237
Authors: Radko Komers; William E Schutzer; John F Reed; Jessie N Lindsley; Terry T Oyama; David C Buck; Scott L Mader; Sharon Anderson Journal: Diabetes Date: 2006-06 Impact factor: 9.461
Authors: Umair Z Malik; Nicholas J Hundley; Guillermo Romero; Rafael Radi; Bruce A Freeman; Margaret M Tarpey; Eric E Kelley Journal: Free Radic Biol Med Date: 2011-04-15 Impact factor: 7.376
Authors: Laura G Sánchez-Lozada; Edilia Tapia; Virgilia Soto; Carmen Avila-Casado; Martha Franco; Jerry L Wessale; Lin Zhao; Richard J Johnson Journal: Nephron Physiol Date: 2008-04-24
Authors: Richard J Johnson; George L Bakris; Claudio Borghi; Michel B Chonchol; David Feldman; Miguel A Lanaspa; Tony R Merriman; Orson W Moe; David B Mount; Laura Gabriella Sanchez Lozada; Eli Stahl; Daniel E Weiner; Glenn M Chertow Journal: Am J Kidney Dis Date: 2018-02-27 Impact factor: 8.860