title: Insulin signaling to the glomerular podocyte is critical for normal kidney function.
abstract: Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Hale
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Eremina
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Jeansson
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maezawa
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lennon
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Pons
authors.affiliation: School of Physics, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Owen
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.affiliation: School of Physics, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Mervyn J
authors.initials: MJ
authors.lastname: Miles
authors.affiliation: Department of Molecular Pharmacology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Caunt
authors.affiliation: Department of Molecular Pharmacology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Craig A
authors.initials: CA
authors.lastname: McArdle
authors.affiliation: Department of Internal Medicine D, Nephrology and Hypertension, University Clinics Muenster, Muenster 48149, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: School of Biochemistry, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavaré
authors.affiliation: Department of Pathology, University Health Network and University of Toronto, Ontario M5G 2C4, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Herzenberg
authors.affiliation: Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada. Electronic address: richard.coward@bristol.ac.uk.
authors.forename: Richard J M
authors.initials: RJM
authors.lastname: Coward
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies; D007328:Insulin / Q000502:physiology*; D007668:Kidney / Q000502:physiology*; D007678:Kidney Glomerulus / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050199:Podocytes / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases