The Human Glomerular Podocyte Is a Novel Target for Insulin Action

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 11; pp. 3095 - 3102
• Main Authors: Coward, Richard J.M., Welsh, Gavin I., Yang, Jing, Tasman, Candida, Lennon, Rachel, Koziell, Ania, Satchell, Simon, Holman, Geoffrey D., Kerjaschki, Dontscho, Tavaré, Jeremy M., Mathieson, Peter W., Saleem, Moin A.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2005
• Subjects: Actins - metabolism; Adipocytes; Albumin; Animals; Antibodies; Biological and medical sciences; Biological Transport - drug effects; Cell Line; Cells; Cytoskeleton; Diabetes; Diabetes research; Diabetes. Impaired glucose tolerance; Diabetic nephropathy; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelial Cells - metabolism; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Silencing; Glucose; Glucose - metabolism; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; Health aspects; Humans; Insulin; Insulin - pharmacology; Insulin resistance; Medical sciences; Mice; Phosphorylation - drug effects; Podocytes - drug effects; Podocytes - metabolism; Podocytes - ultrastructure; Protein Transport; Proteins; Signal Transduction - drug effects; United Kingdom > UK; Ann Arbor Michigan; United States > US; Endocrinopathy; Human; Podocyte; Pancreatic hormone; Insulin; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.11.3095

The Human Glomerular Podocyte Is a Novel Target for Insulin Action Richard J.M. Coward 1 , Gavin I. Welsh 2 , Jing Yang 3 , Candida Tasman 1 , Rachel Lennon 1 , Ania Koziell 4 , Simon Satchell 1 , Geoffrey D. Holman 3 , Dontscho Kerjaschki 5 , Jeremy M. Tavaré 2 , Peter W. Mathieson 1 and Moin A. Saleem 1 1 Academic and Children’s Renal Unit, University of Bristol, U.K 2 Department of Biochemistry, University of Bristol, U.K 3 Department of Biology and Biochemistry, University of Bath, U.K 4 Molecular Medicine Unit, Institute of Child Health, University College, London, U.K 5 Department of Clinical Pathology, University of Vienna, Vienna, Austria Address correspondence and reprint requests to Moin Saleem, Academic and Children’s Renal Unit, University of Bristol, Southmead Hospital, Bristol, U.K. BS10 5NB. E-mail: m.saleem{at}bristol.ac.uk Abstract Microalbuminuria is significant both as the earliest stage of diabetic nephropathy and as an independent cardiovascular risk factor in nondiabetic subjects, in whom it is associated with insulin resistance. The link between disorders of cellular insulin metabolism and albuminuria has been elusive. Here, we report using novel conditionally immortalized human podocytes in vitro and human glomeruli ex vivo that the podocyte, the principal cell responsible for prevention of urinary protein loss, is insulin responsive and able to approximately double its glucose uptake within 15 min of insulin stimulation. Conditionally immortalized human glomerular endothelial cells do not respond to insulin, suggesting that insulin has a specific effect on the podocyte in the glomerular filtration barrier. The insulin response of the podocyte occurs via the facilitative glucose transporters GLUT1 and GLUT4, and this process is dependent on the filamentous actin cytoskeleton. Insulin responsiveness in this key structural component of the glomerular filtration barrier may have central relevance for understanding of diabetic nephropathy and for the association of albuminuria with states of insulin resistance. 2-DOG, 2-deoxy-[3H]d-glucose BCA, bicinchoninic acid F-actin, filamentous-actin RIPA, radioimmunoprecipitation siRNA, small inhibitors of RNA Footnotes Accepted July 25, 2005. Received October 23, 2004. DIABETES