title: High glucose upregulation of early-onset Parkinson's disease protein DJ-1 integrates the PRAS40/TORC1 axis to mesangial cell hypertrophy.
abstract: The Akt kinase signaling pathway is frequently deregulated in many human diseases including cancer, autoimmune disease and diabetes. In nephropathy, associated with diabetes, increased Akt signal transduction results in glomerular especially mesangial cell hypertrophy. The mechanism of Akt activation by elevated glucose is poorly understood. The oncogene DJ-1 prevents oxidative damage and apoptosis of dopaminergic neurons in animal models of Parkinson's disease and in culture. We identified DJ-1 to increase in response to high glucose in renal glomerular mesangial cells concomitant with an increase in phosphorylation of Akt in a time-dependent manner. Plasmid-derived overexpression as well as downregulation of DJ-1 by siRNA showed the requirement of this protein in high glucose-stimulated Akt phosphorylation. The tumor suppressor protein PTEN acts as a negative regulator of Akt activation. Interestingly, DJ-1 was associated with PTEN and this interaction was significantly increased in response to high glucose. High glucose-induced increase in DJ-1 promoted phosphorylation of the PRAS40, a negative regulator of TORC1 kinase activity, resulting in activating and inactivating phosphorylation of S6 kinase and 4EBP-1, respectively. Furthermore, DJ-1 increased protein synthesis and hypertrophy of mesangial cells. Our results provide evidence for a unique mechanism whereby DJ-1 induces Akt/PRAS40/TORC1-mediated hypertrophy in response to high glucose.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, TX, 78229–3900, USA.
authors.forename: Falguni
authors.initials: F
authors.lastname: Das
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Dey
authors.forename: Balachandar
authors.initials: B
authors.lastname: Venkatesan
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D049108:Cell Enlargement; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C516104:Akt1s1 protein, rat; D002352:Carrier Proteins; C519510:Crtc1 protein, rat; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005947:Glucose