Abstract
Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2.
Highlights
The kidney is a vital and complex organ that accomplishes multiple physiological functions in the body, such as metabolic waste excretion, water and electrolyte homeostasis control, acid-base balance and blood pressure maintenance
This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks
We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data
Summary
The kidney is a vital and complex organ that accomplishes multiple physiological functions in the body, such as metabolic waste excretion, water and electrolyte homeostasis control, acid-base balance and blood pressure maintenance. Nephrons’ formation is mainly decided by the interaction of the ureteric bud (UB) and metanephric mesenchyme (MM) cells [3,4] It begins at embryonic day 10.5 (E10.5) to E11.0 when the UB starts growing and branching under the induction of MM cells [5], and MM cells aggregate around the branched tips of UB. Zeb promotes EMT through suppression of CDH1 (encoding E-cadherin, an epithelial maker) and the microRNA-200 [10] This process activates transforming growth factor-β1 (TGF-β1) signaling pathway and trigger cancer cell proliferation, invasiveness and stemness out of control [11,12]. A MET-marker, maintains cap mesenchyme multipotent nephron progenitor cells at an undifferentiated state, promotes MM cell proliferation and restrains cell apoptosis during kidney development [8,9,16]. These discoveries provided theoretical evidence for further studying the role of Zeb1—regulated Six in kidney development
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