Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy.
Am J Physiol Renal Physiol
; 308(9): F993-F1003, 2015 May 01.
Article
em En
| MEDLINE
| ID: mdl-25651569
ABSTRACT
IL-1ß-secreting nucleotide-binding oligomerization domain protein 3 (NLRP3) inflammasomes play a pivotal role in triggering innate immune responses in metabolic disease. We investigated the role of soluble uric acid in NLRP3 inflammasome activation in macrophages to demonstrate the effect of systemic hyperuricemia on progressive kidney damage in type 2 diabetes. THP-1 cells, human acute monocytic leukemia cells, were cultured to obtain macrophages, and HK-2 cells, human renal proximal tubule cells, were cultured and stimulated with uric acid. In vivo, we designed four rat groups as follows 1) Long-Evans Tokushima Otsuka (LETO); 2) Otsuka Long-Evans Tokushima Fatty (OLETF); 3) OLETF+high-fructose diet (HFD) for 16 wk; and 4) OLETF+HFD+allopurinol (10 mg/dl administered in the drinking water). Soluble uric acid stimulated NLRP3 inflammasomes to produce IL-1ß in macrophages. Uric acid-induced MitoSOX mediates NLRP3 activation and IL-1ß secretion. IL-1ß from macrophages activates NF-κB in cocultured proximal tubular cells. In vivo, intrarenal IL-1ß expression and macrophage infiltration increased in HFD-fed OLETF rats. Lowering the serum uric acid level resulted in improving the albuminuria, tubular injury, macrophage infiltration, and renal IL-1ß (60% of HFD-fed OLETF) independently of glycemic control. Direct activation of proximal tubular cells by uric acid resulted in (C-X-C motif) ligand 12 and high mobility group box-1 release and accelerated macrophage recruitment and the M1 phenotype. Taken together, these data support direct roles of hyperuricemia in activating NLRP3 inflammasomes in macrophages, promoting chemokine signaling in the proximal tubule and contributing to the progression of diabetic nephropathy through cross talk between macrophages and proximal tubular cells.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Úrico
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Proteínas de Transporte
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Receptores Citoplasmáticos e Nucleares
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Hiperuricemia
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Diabetes Mellitus Tipo 2
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Nefropatias Diabéticas
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Inflamassomos
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Inflamação
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Túbulos Renais Proximais
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Macrófagos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article