Notch1 regulates PTEN expression to exacerbate renal tubulointerstitial fibrosis in diabetic nephropathy by inhibiting autophagy via interactions with Hes1.

Diabetic nephropathy (DN) is a serious clinical microvascular complication of diabetes mellitus. DN is characterized by the accumulation of extracellular matrix, resulting in progressive fibrosis leading to the loss of renal function. Notch1 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling have been associated with fibrosis. Autophagy serves as an essential regulator of tubular cellular homeostasis. However, how these molecules control the balance between fibrosis and autophagy, the main homeostatic mechanism regulating fibrosis, is not well understood. This association was confirmed using Notch1-siRNA in vitro, which prevented the increase in Hes1 and restored PTEN expression. In contrast, transfection with pHAGE-Hes1 repressed PTEN promoter-driven luciferase activity, implying a direct relationship between Hes1 and PTEN. The expression of Notch1 and Hes1 was increased in diabetic db/db mice by western blotting; in contrast, the expression of PTEN was decreased. Importantly, the dysregulation of these signaling molecules was associated with an increase in extracellular matrix proteins (Collagen-I and III) and the inhibition of autophagy. Similar results were evident in response to high glucose concentrations in vitro in the NRK-52e cells. Therefore, the high glucose concentrations present in diabetes promote fibrosis through the Notch1 pathway via Hes1, while inhibiting the PTEN and autophagy. In conclusion, the inhibition of PTEN by Notch1/Hes1 in response to high glucose concentration inhibits autophagy, which is associated with the progression of fibrosis. Therefore, these signaling molecules may represent novel therapeutic targets in diabetic nephropathy.