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Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes

Nicolas Drapeau1, Farah Lizotte, Benoit Denhez

  • 1Clinical Research Center Étienne Le-Bel and Division of Endocrinology, Departments of Medicine, Université de Sherbrooke, Québec, Canada.

American Journal of Physiology. Endocrinology and Metabolism
|March 28, 2013
PubMed

Insights

High glucose levels in diabetic nephropathy increase SHP-1, causing insulin resistance and podocyte loss. This study reveals SHP-1 (Src homology-2 domain-containing phosphatase-1) as a key factor in kidney damage progression.

Area of Science:

  • Nephrology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic nephropathy (DN) is a major complication of diabetes, characterized by progressive kidney damage.
  • Renal podocyte apoptosis is an early indicator of DN progression, and insulin signaling is vital for podocyte survival.
  • Previous research indicated elevated Src homology-2 domain-containing phosphatase-1 (SHP-1) in the renal cortex of type 1 diabetic mice.

Purpose of the Study:

  • To investigate the role of hyperglycemia-induced SHP-1 expression in affecting insulin actions within podocytes.
  • To elucidate the mechanism by which SHP-1 contributes to podocyte apoptosis and insulin resistance in diabetic nephropathy.

Main Methods:

  • Utilized type 1 diabetic Akita mice and control littermates for in vivo studies.
  • Employed cultured podocytes exposed to high glucose concentrations (HG) for in vitro experiments.
  • Assessed podocyte apoptosis, foot process effacement, insulin signaling pathways (Akt, ERK phosphorylation), and SHP-1 expression levels.

Main Results:

  • Akita mice exhibited increased podocyte apoptosis and foot process effacement compared to controls.
  • Renal podocytes in Akita mice showed reduced insulin-stimulated Akt and ERK phosphorylation, associated with elevated glomerular SHP-1.
  • High glucose exposure in cultured podocytes increased SHP-1 expression, induced apoptosis, and impaired insulin signaling; these effects were reversed by dominant-negative SHP-1.
  • Elevated SHP-1 directly interacted with insulin receptor-β, inhibiting insulin-stimulated Akt and ERK phosphorylation.

Conclusions:

  • High levels of SHP-1 expression in glomeruli contribute to insulin resistance and podocyte loss in diabetic nephropathy.
  • Hyperglycemia-induced SHP-1 is a critical mediator of podocyte injury and a potential therapeutic target for diabetic kidney disease.
Keywords:
Src homology-2 domain-containing phosphatase-1insulin receptor-βinsulin signalingprotein tyrosine phosphatase

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