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Effects of xanthine oxidase inhibition with febuxostat on the development of
nephropathy in experimental type 2 diabetes
#MMPMID27238746
Komers R
; Xu B
; Schneider J
; Oyama TT
Br J Pharmacol
2016[Sep]; 173
(17
): 2573-88
PMID27238746
show ga
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.
|Animals
[MESH]
|Cells, Cultured
[MESH]
|Diabetes Mellitus, Type 2/*complications/drug therapy/metabolism
[MESH]
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