title: Insulin-like growth factor-I induces renal cell hypertrophy via a calcineurin-dependent mechanism.
abstract: Insulin-like growth factor-I (IGF-I) may play an important role in the development of renal hypertrophy. In this study we determined the effect of IGF-I on cultured mesangial cells (MCs) and examined activation of key signaling pathways. IGF-I induced hypertrophy as determined by an increase in cell size and an increase in protein to DNA ratio and increased accumulation of extracellular matrix (ECM) proteins. IGF-I also activated both Erk1/Erk2 MAPK and phosphatidylinositol 3-kinase (PI3K) in MCs. Inhibition of either MAPK or PI3K, however, had no effect on IGF-I-induced hypertrophy or ECM production. Next, we examined the effect of IGF-I on activation of the calcium-dependent phosphatase calcineurin. IGF-I treatment stimulated calcineurin activity and increased the protein levels of calcineurin and the calcineurin binding protein, calmodulin. Cyclosporin A, an inhibitor of calcineurin, blocked both IGF-I-mediated hypertrophy and up-regulation of ECM. In addition, calcineurin resulted in sustained Akt activation, indicating possible cross-talk with other signaling pathways. Finally, IGF-I treatment resulted in the calcineurindependent nuclear localization of NFATc1. Therefore, IGF-I induces hypertrophy and increases ECM accumulation in MCs. IGF-I-mediated hypertrophy is associated with activation of Erk1/Erk2 MAPK and PI3K but does not require either of these pathways. Instead, IGF-I mediates hypertrophy via a calcineurin-dependent pathway.
authors.affiliation: South Texas Veterans Health Care System, Audie Murphy Division, San Antonio, Texas 78229, USA. gooch@uthscsa.edu
authors.forename: J L
authors.initials: JL
authors.lastname: Gooch
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.forename: J M
authors.initials: JM
authors.lastname: Ricono
authors.forename: H E
authors.initials: HE
authors.lastname: Abboud
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000633:toxicity
chemical_list: D019703:Calcineurin; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C494920:Akt1 protein, rat