title: ID1 inhibits USF2 and blocks TGF-β-induced apoptosis in mesangial cells.
abstract: Mesangial cells (MC) play an essential role in normal function of the glomerulus. Phenotypic changes in MC lead to the development of glomerular diseases such as diabetic nephropathy and glomerulosclerosis. The late phase of diabetic glomerulopathy is characterized by MC death and fibrosis. Current data highlight the transforming growth factor (TGF)-β as a trigger of the pathological changes observed in MC, including death by apoptosis. However, the mechanisms and mediators involved in this process are still poorly understood. Identification of novel elements involved in MC death may provide a better understanding of the pathophysiology of glomerular diseases. Here, we show that bone morphogenetic proteins (BMPs; known antagonists of the profibrotic effects of TGF-β in the kidney) strongly induce inhibitor of DNA binding (ID1) mRNA transcription and protein expression in human MC. ID genes have been implicated in cell survival control and are constitutively expressed in MC. We show that BMPs and ID1 exert an anti-apoptotic effect in MC by inhibition of USF2 transcriptional activity. On the other hand, TGF-β upregulates USF2, increasing BAX (proapoptotic gene) levels and apoptosis rates. Taken together, our results point to a novel molecular pathway that modulates MC apoptosis, which is potentially involved in the pathogenesis of glomerular diseases.
authors.affiliation: Department of Physiology and Biophysics, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Albert Einstein, 627 Morumbi, São Paulo, SP, Brazil.
authors.forename: Alex Yuri Simões
authors.initials: AY
authors.lastname: Sato
authors.forename: Eliane
authors.initials: E
authors.lastname: Antonioli
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Tambellini
authors.forename: Alexandre Holthausen
authors.initials: AH
authors.lastname: Campos
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051720:Upstream Stimulatory Factors / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: C494826:BAX protein, human; D019485:Bone Morphogenetic Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016212:Transforming Growth Factor beta; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; D051028:bcl-2-Associated X Protein