title: Persistent Insulin Resistance in Podocytes Caused by Epigenetic Changes of SHP-1 in Diabetes.
abstract: Poor glycemic control profoundly affects protein expression and the cell signaling action that contributes to glycemic memory and irreversible progression of diabetic nephropathy (DN). We demonstrate that SHP-1 is elevated in podocytes of diabetic mice, causing insulin unresponsiveness and DN. Thus, sustained SHP-1 expression caused by hyperglycemia despite systemic glucose normalization could contribute to the glycemic memory effect in DN. Microalbuminuria, glomerular filtration rate, mesangial cell expansion, and collagen type IV and transforming growth factor-β expression were significantly increased in diabetic Ins2+/C96Ymice compared with nondiabetic Ins2+/+mice and remained elevated despite glucose normalization with insulin implants. A persistent increase of SHP-1 expression in podocytes despite normalization of systemic glucose levels was associated with sustained inhibition of the insulin signaling pathways. In cultured podocytes, high glucose levels increased mRNA, protein expression, and phosphatase activity of SHP-1, which remained elevated despite glucose concentration returning to normal, causing persistent insulin receptor-β inhibition. Histone posttranslational modification analysis showed that the promoter region of SHP-1 was enriched with H3K4me1 and H3K9/14ac in diabetic glomeruli and podocytes, which remained elevated despite glucose level normalization. Hyperglycemia induces SHP-1 promoter epigenetic modifications, causing its persistent expression and activity and leading to insulin resistance, podocyte dysfunction, and DN.
authors: Research Center of CHU de Sherbrooke and Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.|Division of Endocrinology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Farah
authors: F
authors: Lizotte
authors: Research Center of CHU de Sherbrooke and Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.|Division of Endocrinology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Benoit
authors: B
authors: Denhez
authors: Research Center of CHU de Sherbrooke and Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.|Division of Endocrinology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Andréanne
authors: A
authors: Guay
authors: Department of Biology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Nicolas
authors: N
authors: Gévry
authors: Research Center of CHU de Sherbrooke and Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.|Department of Nephrology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Anne Marie
authors: AM
authors: Côté
authors: Research Center of CHU de Sherbrooke and Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada pedro.geraldes@usherbrooke.ca.|Division of Endocrinology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Pedro
authors: P
authors: Geraldes
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005919:Glomerular Filtration Rate / Q000502:physiology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D011972:Receptor, Insulin; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse