ERK and p38 MAPK inhibition controls NF-E2 degradation and profibrotic signaling in renal proximal tubule cells.
Life Sci
; 287: 120092, 2021 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-34715142
ABSTRACT
AIMS:
Transforming growth factor-ß (TGF-ß) mediates fibrotic manifestations of diabetic nephropathy. We demonstrated proteasomal degradation of anti-fibrotic protein, nuclear factor-erythroid derived 2 (NF-E2), in TGF-ß treated human renal proximal tubule (HK-11) cells and in diabetic mouse kidneys. The current study examined the role of mitogen-activated protein kinase (MAPK) pathways in mediating NF-E2 proteasomal degradation and stimulating profibrotic signaling in HK-11 cells. MAINMETHODS:
HK-11 cells were pretreated with vehicle or appropriate proteasome and MAPK inhibitors, MG132 (0.5 µM), SB203580 (1 µM), PD98059 (25 µM) and SP600125 (10 µM), respectively, followed by treatment with/without TGF-ß (10 ng/ml, 24 h). Cell lysates and kidney homogenates from FVB and OVE26 mice treated with/without MG132 were immunoblotted with appropriate antibodies. pUse vector and pUse-NF-E2 cDNA were transfected in HK-11 cells and effects of TGF-ß on JNK MAPK phosphorylation (pJNK) was examined. KEYFINDINGS:
We demonstrated activation of p38, ERK, and JNK MAPK pathways in TGF-ß treated HK-11 cells. Dual p38 and ERK MAPK blockade prevented TGF-ß-induced pSer82Hsp27, fibronectin and connective tissue growth factor (CTGF) expression while preserving NF-E2 expression. Blockade of JNK MAPK inhibited TGF-ß-induced CTGF expression without preserving NF-E2 expression. MG132 treatment prevented TGF-ß-induced pJNK in HK-11 cells and in type 1 diabetic OVE26 mouse kidneys, demonstrating that TGF-ß- and diabetes-induced pJNK occurs downstream of proteasome activation. A direct role for NF-E2 in modulating pJNK activation was demonstrated by NF-E2 over-expression.SIGNIFICANCE:
ERK and p38 MAPK promotes NF-E2 proteasomal degradation while proteasome activation promotes pJNK and profibrotic signaling in renal proximal tubule cells.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Sistema de Sinalização das MAP Quinases
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Proteínas Quinases p38 Ativadas por Mitógeno
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Subunidade p45 do Fator de Transcrição NF-E2
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Túbulos Renais Proximais
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article