FIH-1调控的HIF-1αC端转录激活区介导小管间质纤维化发生的机制研究

小管间质纤维化（TIF）是肾脏病进行性进展的关键病理改变，但其发病机制仍不十分清楚。课题组近年来发现，小管上皮细胞（TEC）在TIF形成中发挥重要驱动作用，而HIF-1异常活化是导致TEC损伤的重要因素（Li ZL* and Lv LL*, Kidney Int, 2019）。预实验发现，TIF与HIF-1异常活化密切相关。基因组测序及验证实验提示，KLF5活化是HIF-1介导TIF发生关键新机制，而FIH-1调控的HIF-1αC端转录激活区（C-TAD）可能是决定KLF5能否被转录的关键。为此，拟提出如下科研假说：缺氧诱导FIH-1抑制，引起HIF-1αC-TAD激活，后者促进KLF5转录活化和TIF发生。本研究拟通过动物模型和C-TAD基因条件性敲除等手段，探讨FIH-1调控HIF-1αC-TAD-KLF5通路在缺氧所致TIF中的作用，以阐明缺氧导致TIF的关键机制，为临床TIF防治提供新颖理论依据。

The tubulointerstitial fibrosis (TIF) is a key factor promoting the progression of kidney diseases. However, the exact mechanism remains unclear. Recently, our team demonstrates that renal tubule injury is a driving force toward TIF. Moreover, hypoxia-induced hypoxia inducible factor-1 (HIF-1) activation is the critical factor contributing to tubule injury (Li ZL* and Lv LL*, Kidney Int, 2019). Our preliminary data showed that the time-course of tubule HIF-1 activation was closely associated with hypoxia induced TIF. Genome-wide RNA-sequences analysis and combined with in vivo and in vitro experiments suggested that the KLF5 activation was the key mechanism of HIF-1-mediated TIF development, whereas the FIH-1 mediated HIF-1αC-terminal transcriptional activation domain (C-TAD) was the key factor for determining the transcriptional activation of KLF5. Therefore, we hypothesized that during the development of TIF, severe hypoxia caused the functional inhibition of FIH-1, which led to activation of HIF-1αC-TAD to induce KLF5 pathway activation in tubule, and TIF developed. To explore this hypothesis, we will investigate the role of FIH-1-regulated HIF-1αC-TAD-KLF5 activation in TIF by hypoxia-induced TIF animal model, during which the C-TAD conditional knockout mice will be involved. The present study will not only elucidate the exact mechanism of hypoxia-induced TIF, also provide the new targets for prevention of TIF development.