The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-ß1 expressions in rat glomerular mesangial cells.
Exp Cell Res
; 361(1): 63-72, 2017 12 01.
Article
en En
| MEDLINE
| ID: mdl-28986066
ABSTRACT
Oxidative stress aroused by advanced glycation-end products (AGEs) is a culprit in the pathological progression of diabetic nephropathy. Both Sirt1 and the Keap1/Nrf2/ARE anti-oxidative pathway exert crucial inhibitory effects on the development of diabetic nephropathy. Our previous study has confirmed that Sirt1 activation can inhibit the upregulation of fibronectin (FN) and transforming growth factor-ß1 (TGF-ß1) by promoting Keap1/Nrf2/ARE pathway in glomerular mesangial cells (GMCs) challenged with AGEs. However, the underlying mechanism needs further investigation. Here, we found that concomitant with deacetylating and reducing the ubiquitination levels of Nrf2, Sirt1 significantly enhanced the activity of Keap1/Nrf2/ARE pathway including decreasing Keap1 expression, promoting the nuclear content, ARE-binding ability, and transcriptional activity of Nrf2, augmenting the protein levels of heme oxygenase 1, a target gene of Nrf2, which eventually quenched ROS overproduction and alleviating FN and TGF-ß1 accumulation in AGEs-treated GMCs. And depletion of Nrf2 blocked those renoprotective effects of Sirt1. Interestingly, Nrf2 also positively regulated Sirt1 at the protein expression and deacetylase activity levels as evidenced by tert-Butylhydroquinone and specific siRNA targeting Nrf2 to downregulate FN and TGF-ß1. In conclusion, the current study basically demonstrated that the crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit the protein expressions of FN and TGF-ß1 in AGEs-treated GMCs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hidrolasas de Éster Carboxílico
/
Fibronectinas
/
Células Mesangiales
/
Factor 2 Relacionado con NF-E2
/
Factor de Crecimiento Transformador beta1
/
Sirtuina 1
/
Proteína 1 Asociada A ECH Tipo Kelch
/
Glomérulos Renales
Límite:
Animals
Idioma:
En
Revista:
Exp Cell Res
Año:
2017
Tipo del documento:
Article