Persistent Insulin Resistance in Podocytes Caused by Epigenetic Changes of SHP-1 in Diabetes
Poor glycemic control profoundly impacts protein expression and cell signaling action that contributes to glycemic memory and irreversible progression of diabetic nephropathy (DN). We have demonstrated 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, GFR, mesangial cell expansion, collagen IV and TGF-β expression were significantly increased in diabetic Ins2+/C96Y mice compared to non-diabetic Ins2+/+ mice and remained elevated despite glucose normalization with insulin implants. Persistent increase of SHP-1 expression in podocytes in spite of normalization of systemic glucose levels was associated with sustained inhibition of the insulin signaling pathways. In cultured podocytes, high glucose levels (HG) increased mRNA, protein expression and phosphatase activity of SHP-1 which remained elevated despite returning glucose concentration to normal glucose (NG) causing persistent insulin receptor beta inhibition. Histone post-translational 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 normalisation. In conclusion, hyperglycemia induces SHP-1 promoter epigenetic modifications causing its persistent expression and activity leading to insulin resistance, podocyte dysfunction and DN.
- Received February 23, 2016.
- Accepted August 25, 2016.
- © 2016 by the American Diabetes Association.