title: The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes.
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.
authors.affiliation: The University of Texas Health Science Center, Department of Medicine-MSC 7882, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. habib@uthscsa.edu
authors.forename: Chakradhar
authors.initials: C
authors.lastname: Velagapudi
authors.forename: Basant S
authors.initials: BS
authors.lastname: Bhandari
authors.forename: Sherry
authors.initials: S
authors.lastname: Abboud-Werner
authors.forename: Simona
authors.initials: S
authors.lastname: Simone
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.forename: Samy L
authors.initials: SL
authors.lastname: Habib
mesh_terms: D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D008297:Male; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000502:physiology*; D013311:Streptozocin; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat; D013311:Streptozocin; D011065:Poly(ADP-ribose) Polymerases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases