The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes.
J Am Soc Nephrol
; 22(2): 262-73, 2011 Feb.
Article
en En
| MEDLINE
| ID: mdl-21289215
ABSTRACT
Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose (HG) induces apoptosis is not fully understood. Because the tuberin/mTOR pathway can modulate apoptosis, we studied the role of this pathway in apoptosis in type I diabetes and in cultured proximal tubular epithelial (PTE) cells exposed to HG. Compared with control rats, diabetic rats had more apoptotic cells in the kidney cortex. Induction of diabetes also increased phosphorylation of tuberin in association with mTOR activation (measured by p70S6K phosphorylation), inactivation of Bcl-2, increased cytosolic cytochrome c expression, activation of caspase 3, and cleavage of PARP; insulin treatment prevented these changes. In vitro, exposure of PTE cells to HG increased phosphorylation of tuberin and p70S6K, phosphorylation of Bcl-2, expression of cytosolic cytochrome c, and caspase 3 activity. High glucose induced translocation of the caspase substrate YY1 from the cytoplasm to the nucleus and enhanced cleavage of PARP. Pretreatment the cells with the mTOR inhibitor rapamycin reduced the number of apoptotic cells induced by HG and the downstream effects of mTOR activation noted above. Furthermore, gene silencing of tuberin with siRNA decreased cleavage of PARP. These data show that the tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes, mediated in part by cleavage of PARP by YY1.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Proteínas Supresoras de Tumor
/
Diabetes Mellitus Experimental
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Diabetes Mellitus Tipo 1
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Serina-Treonina Quinasas TOR
/
Túbulos Renales Proximales
Límite:
Animals
Idioma:
En
Revista:
J Am Soc Nephrol
Asunto de la revista:
NEFROLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos