Nephrin is critical for the action of insulin on human glomerular podocytes

Richard J M Coward, Gavin I Welsh, Ania Koziell, Sagair Hussain, Rachel Lennon, Lan Ni, Jeremy M Tavaré, Peter W Mathieson, Moin A Saleem

Research output: Contribution to journalArticle (Academic Journal)

112 Citations (Scopus)

Abstract

The leading causes of albuminuria and end-stage renal failure are secondary to abnormalities in the production or cellular action of insulin, including diabetes and hyperinsulinemic metabolic syndrome. The human glomerular podocyte is a critical cell for maintaining the filtration barrier of the kidney and preventing albuminuria. We have recently shown this cell to be insulin sensitive with respect to glucose uptake, with kinetics similar to muscle cells. We now show that the podocyte protein nephrin is essential for this process. Conditionally immortalized podocytes from two different patients with nephrin mutations (natural human nephrin mutant models) were unresponsive to insulin. Knocking nephrin down with siRNA in wild-type podocytes abrogated the insulin response, and stable nephrin transfection of nephrin-deficient podocytes rescued their insulin response. Mechanistically, we show that nephrin allows the GLUT1- and GLUT4-rich vesicles to fuse with the membrane of this cell. Furthermore, we show that the COOH of nephrin interacts with the vesicular SNARE protein VAMP2 in vitro and ex vivo (using yeast-2 hybrid and coimmunoprecipitation studies). This work demonstrates a previously unsuspected role of nephrin in vesicular docking and insulin responsiveness of podocytes.

Original languageEnglish
Pages (from-to)1127 - 1135
Number of pages9
JournalDiabetes
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2007

Bibliographical note

Publisher: American Diabetes Association

Keywords

  • Biological Transport
  • Child
  • Deoxyglucose
  • Humans
  • Kidney Failure, Chronic
  • Kidney Glomerulus
  • Membrane Proteins
  • Nephrotic Syndrome
  • Podocytes
  • RNA, Small Interfering
  • Vesicle-Associated Membrane Protein 2

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