Notch signaling in the collecting duct regulates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice

ABSTRACT

BACKGROUND/AIMS: Mind bomb-1 (Mib1) encodes an E3 ubiquitin ligase, which is required for the initiation of Notch signaling. Recently, it was demonstrated that the renal collecting duct plays an important role in renal fibrosis. Here, we investigated the role of Notch signaling in renal fibrosis using conditional knockout mice with the specific ablation of Mib1 in renal collecting duct principal cells. METHODS: Mib1-floxed mice (Mib1f/f ) were crossed with aquaporin 2 (AQP2)-Cre mice in order to generate principal cell-specific Mib1 knockout mice (Mib1f/fAQP2-Cre+). Unilateral ureteral obstruction (UUO) was performed, and mice were sacrificed 7 days after UUO. RESULTS: After performing the UUO, renal tubulointerstitial fibrosis and the expression of transforming growth factor β were markedly enhanced in the obstructed kidneys of Mib1f/f mice compared with the sham-operated kidney of Mib1f/f mice. These changes were shown to be even more pronounced in the obstructed kidneys of Mib1f/fAQP2-Cre+ mice than in those of the Mib1f/f mice . Furthermore, the number of TUNNEL-positive cells in renal collecting duct was higher in the obstructed kidneys of Mib1f/fAQP2-Cre+ mice than in the kidneys of Mib1f/f mice. CONCLUSIONS: Notch signaling in the renal collecting duct plays an important role in the regulation of renal tubulointerstitial fibrosis and apoptosis after UUO.