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The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model

井上賢紀広島大学

2020.03.23

概要

The search for methods of preventing chronic kidney disease (CKD) progression is still an
important and ongoing challenge [1]. Usually, lifestyle and dietary modifications aimed at reducing
sodium intake as well as renin-angiotensin-aldosterone system blockers are recommended [2–4].
On the other hand, several recent clinical studies have suggested that xanthine oxidase inhibitors (XOi),
including febuxostat, beneficially inhibit CKD progression [5]. Experimentally, febuxostat also exerts
direct renal benefits, independently of its uric acid (UA) lowering effect [6–9]. Although reduction
of oxidative stress by XO inhibition might be involved in the underlying mechanism, clear evidence
has not as yet been obtained. At present, the diseases impacted by the preventive effects of XOi on
renal failure progression, which appear to include diabetes mellitus, glomerular sclerosis, chronic
glomerulonephritis, and various autoimmune disorders, remain to be fully clarified.
IgA nephropathy is a kidney disease characterized by deposition of immunoglobulin A (IgA) in
the glomeruli. This results in local chronic inflammation, leading to glomerular injury and impairment
of renal functions such as filtration [10]. The courses of IgA nephropathy vary greatly among
patients, although approximately 30% will have end-stage renal disease within 20 years of the initial
diagnosis [11]. At present, there is no definitive cure for IgA nephropathy, with blood pressure control
and/or the usage of anti-inflammatory agents such as steroids only slowing its progression [12–15].
We investigated the effects of febuxostat, one of the widely used XOis, on the development of IgA
nephropathy, using gddY mice, a rodent model of spontaneous IgA nephropathy [16]. Unlike HIGA
mice showing only mild proteinuria without hematuria, gddY mice exhibit an early onset of glomerular
IgA deposition and clinicopathological aberrations other than hematuria, features resembling those of
human IgA nephropathy [17]. To date, neither clinical nor basic research has been carried out regarding
the efficacy of XOi as a treatment for IgA nephropathy. Thus, to our knowledge, this is the first study
to demonstrate the benefits of XOis for treating IgA nephropathy. In particular, febuxostat treatment
markedly suppressed inflammation and the resultant collagen deposition in the kidneys of gddY mice.
These results suggest the potential of febuxostat as a treatment for human IgA nephropathy.
2. Results
2.1. Xanthine Oxidase Inhibitor Febuxostat Prevents Progression of IgA Nephropathy
Sixteen nine-week-old female gddY mice were divided into two groups and were given water
either with (15 µg/mL) or without febuxostat (Figure 1A). At nine weeks after the initiation of
febuxostat, four of the eight untreated gddY mice had died, while all eight gddY mice receiving
febuxostat in their drinking water survived (Figure 1B). Although a previous report indicated gddY
mice to have a higher death rate than normal mice [18], the death rate of untreated gddY mice in the
present study exceeded our expectations. We speculate that these deaths were due to renal failure
but have no proof. Fortunately, there were four untreated gddY mice that survived and appeared to
be as healthy as the febuxostat-treated gddY mice and the normal control mice, judging from their
activities and other parameters. Thus, the following experiments were performed by analyzing three
groups, i.e., the four untreated gddY, eight febuxostat-treated gddY and eight normal BALB/c mice.
While the gddY mice weighed significantly more than BALB/c mice, febuxostat treatment did not
affect the weights of gddY mice (Figure 1C). Serum uric acid concentration was significantly lowered
in febuxostat-treated gddY mice compared to untreated gddY mice (Figure 1D). Serum IgA levels
showed large variations among individual mice, but differences among the three groups were not
significant (Figure 1E). ...

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The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model

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