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Abstract: SA-PO211

Loss of DUSP4 Promotes Insulin Resistance in Podocytes through JNK Activation

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology


  • Denhez, Benoit, University of Sherbrooke, Sherbrooke, Quebec, Canada
  • Rousseau, Marina, University of Sherbrooke, Sherbrooke, Quebec, Canada
  • Lizotte, Farah, University of Sherbrooke, Sherbrooke, Quebec, Canada
  • Auger-Messier, Mannix, Université de Sherbrooke, Sherbrooke, Quebec, Canada
  • Cote, Anne-Marie, CHUS - Hopital Fleurimont, Sherbrooke, Quebec, Canada
  • Geraldes, Pedro Miguel, University of Sherbooke, Sherbrooke, Alberta, Canada

Diabetic nephropathy is characterized by early damages to podocytes which lead to their dysfunction and loss. Insulin action in podocytes has been shown to be essential for their integrity. Multiple evidences suggested that the activation of JNK can lead to insulin resistance in various cell types. Data from our laboratory showed that the expression of DUSP4, a protein known to inhibit JNK, is reduced in the renal cortex of type 1 diabetic mice and cultured podocytes exposed to high glucose levels. Deletion of DUSP4 in diabetic mice resulted in significant increase of albuminuria, podocyte apoptosis and activation of JNK. The objective is to evaluate the effect of JNK activation induced by the loss of DUSP4 expression on insulin signaling pathway in cultured podocytes exposed to high glucose and diabetic mice.


Non-diabetic (NDM) and diabetic (DM) mice with the deletion of DUSP4 (D4KO) were stimulated with insulin to evaluate its downstream signaling pathway on the activation of IRS1 and Akt in the renal cortex. Mouse podocytes were exposed to normal (NG; 5.6 mM) or high (HG; 25 mM) glucose levels for 72 hours with or without the overexpression of DUSP4 adenoviral vector to evaluate the phosphorylation of JNK and the insulin signaling pathway.


Insulin-stimulated Akt and ERK phosphorylation in the renal cortex of DM mice was decreased compared to NDM mice, and was further reduced in DM D4KO mice. Loss of insulin effects in DM D4KO mice was associated with increased phospho-serine 307 of IRS-1, which is known to inhibit IRS1 activity. In cultured podocytes, HG exposure inhibited insulin-induced activation of Akt, which was associated with a reduction in DUSP4 expression and a 2.8 fold increase in phospho-serine 307 of IRS-1. Overexpression of DUSP4 prevented both the HG-induced increased phosphorylation of JNK and phospho-serine 307 of IRS-1, and restored insulin-stimulated Akt activation in podocytes.


In conlusion, the reduction of DUSP4 expression by hyperglycemia in podocytes contributed to insulin resistance by promoting JNK activation.


  • Government Support - Non-U.S.