title: IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes.
abstract: Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2(-/-)). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2(-/-) podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2(-/-) podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, (CIBERDEM) ISCIII, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santamaria
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom.
authors.forename: Eva
authors.initials: E
authors.lastname: Marquez
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom.
authors.forename: Abigail
authors.initials: A
authors.lastname: Lay
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: RoseaMarie M
authors.initials: RM
authors.lastname: Carew
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, (CIBERDEM) ISCIII, Spain.
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom.
authors.forename: Lan
authors.initials: L
authors.lastname: Ni
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom.
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Hale
authors.affiliation: Instituto de Investigación Sanitaria-Fundación Jiménez-Díaz, Madrid, Spain; Red de Investigación de Enfermedades Renales (REDINREN), ISCIII, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Derek P
authors.initials: DP
authors.lastname: Brazil
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS2 8BJ, United Kingdom. Electronic address: Richard.Coward@bristol.ac.uk.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Coward
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, (CIBERDEM) ISCIII, Spain. Electronic address: avalverde@iib.uam.es.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000502:physiology*; D007333:Insulin Resistance; D007678:Kidney Glomerulus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Diabetic nephropathy; Glucose uptake; Insulin signaling; Podocytes