Early targets of lithium in rat kidney inner medullary collecting duct include p38 and ERK1/2.
Kidney Int
; 86(4): 757-67, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-24786704
ABSTRACT
Almost half of patients receiving lithium salts have nephrogenic diabetes insipidus. Chronic lithium exposure induces AQP2 downregulation and changes in the cellular composition of the collecting duct. In order to understand these pathophysiological events, we determined the earliest lithium targets in rat inner medullary collecting duct (IMCD) by examining changes in the IMCD phosphoproteome after acute lithium administration. IMCDs were isolated 9 h after lithium exposure, a time when urinary concentrating impairment was evident. We found 1093 unique phosphopeptides corresponding to 492 phosphoproteins identified and quantified by mass spectrometry. Label-free quantification identified 152 upregulated and 56 downregulated phosphopeptides in response to lithium. Bioinformatic analysis highlighted several signaling proteins including MAP kinases and cell-junction proteins. The majority of the upregulated phosphopeptides contained a proline-directed motif, a known target of MAPK. Four hours after lithium exposure, phosphorylation sites in the activation loops of ERK1/2 and p38 were upregulated. Increased expression of phospho-Ser261-AQP2 (proline-directed motif) was concomitant with the increase in urine output. Pretreatment with MAPK inhibitors reversed the increased Ser261-AQP2 phosphorylation. Thus, in IMCD, ERK1/2 and p38 are early targets of lithium and may play a role in the onset of lithium-induced polyuria.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Compostos de Lítio
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Proteína Quinase 1 Ativada por Mitógeno
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Sistema de Sinalização das MAP Quinases
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Proteoma
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Proteínas Quinases p38 Ativadas por Mitógeno
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Túbulos Renais Coletores
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article