title: Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes.
abstract: Renal podocyte apoptosis is an early event of diabetic nephropathy progression. Insulin action is critical for podocyte survival. Previous studies demonstrated that Src homology-2 domain-containing phosphatase-1 (SHP-1) is elevated in renal cortex of type 1 diabetic mice; we hypothesized that hyperglycemia-induced SHP-1 expression may affect insulin actions in podocytes. Type 1 diabetic Akita mice (Ins2(+/C96Y)) developed elevated foot process effacement and podocyte apoptosis compared with control littermate mice (Ins2(+/+)). In contrast to Ins2(+/+) mice, insulin-stimulated protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were remarkably reduced in renal podocytes of Akita mice. This renal insulin resistance was associated with elevated SHP-1 expression in the glomeruli. Cultured podocytes exposed to high glucose concentration (HG; 25 mM) for 96 h exhibited high levels of apoptotic markers and caspase-3/7 enzymatic activity. HG exposure raised mRNA and protein levels of SHP-1 and reduced the insulin-signaling pathway in podocytes. Overexpression of dominant-negative SHP-1 in podocytes prevented HG effects and restored insulin actions. Elevated SHP-1 expression induced by high glucose levels was directly associated with insulin receptor-β in vitro and in vivo to prevent insulin-stimulated Akt and ERK phosphorylation. In conclusion, our results showed that high levels of SHP-1 expression in glomeruli cause insulin resistance and podocyte loss, thereby contributing to diabetic nephropathy.
authors.affiliation: Clinical Research Center Étienne Le-Bel and Division of Endocrinology, Departments of Medicine, Université de Sherbrooke, Québec, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Drapeau
authors.forename: Farah
authors.initials: F
authors.lastname: Lizotte
authors.forename: Benoit
authors.initials: B
authors.lastname: Denhez
authors.forename: Andréanne
authors.initials: A
authors.lastname: Guay
authors.forename: Chris R
authors.initials: CR
authors.lastname: Kennedy
authors.forename: Pedro
authors.initials: P
authors.lastname: Geraldes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D007328:Insulin; D011972:Receptor, Insulin; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D053148:Caspase 3; D005947:Glucose
keywords: Src homology-2 domain-containing phosphatase-1; insulin receptor-β; insulin signaling; protein tyrosine phosphatase