UHRF1通过负调控Notch信号通路在FSGS足细胞损伤中的保护作用

Focal segmental glomerulo sclerosis (FSGS) is a common glomerular disease in children and adult nephrotic syndrome (NS) and it is one of the main causes of end stage renal disease (ESRD). Although the pathophysiological mechanism of FSGS remains unclear, podocyte injury plays an important role in the occurrence and development of FSGS. Recent research have suggested that ubiquitin-like with PHD and ring finger domains1( UHRF1) is involved in the development of kidney diseases. UHRF1 is a regulator of DNA methylation and histone ubiquitination, playing an important role in embryonic development and tumorigenesis, but the function of UHRF1 in FSGS is not very clear. Our preliminary studies showed that the expression of UHRF1 was significantly reduced in the kidney from adriamycin nephropathy and renal biopsy tissues of FSGS patients. Meanwhile, the reduction of UHRF1 was cell-specific under adriamycin stimulation, UHRF1 deletion exacerbates podocyte injury in mice with adriamycin treatment, overexpression of UHRF1 attenuated podocyte apoptosis, ameliorated actin cytoskeleton derangement and inhibited the expression of Notch1 in podocytes with adriamycin treatment. These finding indicate that UHRF1 participates in the occurrence and development of FSGS. Therefore, the present study is designed to explore the regulatory effect of UHRF1 in FSGS and investigate UHRF1-Notch signaling pathway in podocyte both in vitro and in vivo animal studies using podocyte-specific deletion of UHRF1 mice. We then evaluated the possibility of up-regulating UHRF1 by adeno-associated virus as a therapeutic drug for the treatment of FSGS. In this study, we postulate that UHRF1 is a major modulator of Notch signaling pathway in podocyte apoptosis representing a putative target to ameliorate human renal podocyte injury.

局灶性节段性肾小球硬化（FSGS）病理生理机制尚不明晰，但肾小球足细胞损伤是促进其发生发展的重要始动因素。最新研究表明，UHRF1参与肾脏疾病的发生。表观遗传调节因子UHRF1是DNA甲基化和组蛋白泛素化的调控因子，在胚胎的发育及肿瘤的发生中扮演重要角色，但在肾脏疾病中的作用知之甚少。我们前期工作证实，UHRF1在FSGS足细胞中表达显著降低并加重足细胞损伤，过表达UHRF1明显减少足细胞凋亡并抑制Notch1的表达。为此，本课题将以UHRF1为中心，运用cre-loxp技术构建足细胞UHRF1敲除小鼠等手段深入研究UHRF1在FSGS足细胞损伤中的作用及探讨UHRF1-Notch信号通路在足细胞中的分子调控机制；并进一步以腺相关病毒为载体过表达UHRF1作为FSGS治疗手段的初步探究。本课题将拓展UHRF1生物学功能新认识，并为临床治疗FSGS提供新的靶点，具有重要理论价值。

局灶性节段性肾小球硬化（FSGS）病理生理机制尚不明晰，但肾小球足细胞损伤是促进其发生发展的重要始动因素。最新研究表明，UHRF1参与肾脏疾病的发生。表观遗传调节因子UHRF1是DNA 甲基化和组蛋白泛素化的调控因子，在胚胎的发育及肿瘤的发生中扮演重要角色，但在肾脏疾病中的作用知之甚少。基于以上研究背景，本课题从临床问题出发，以UHRF1为中心，运用多种技术手段证明了其与FSGS肾损伤的关系，研究成果如下：首先发现UHRF1在FSGS足细胞中表达显著降低并加重足细胞损伤，过表达UHRF1明显减少足细胞凋亡并抑制UBE2S的表达。其次运用cre-loxp技术构建足细胞UHRF1敲除小鼠等手段揭示了UHRF1在FSGS足细胞损伤中的作用并阐明了UHRF1-UBE2S-HIF-1α-氧化应激信号通路在足细胞中的分子调控机制。最后进一步以腺相关病毒为载体过表达UHRF1，证明其对FSGS肾损伤有一定的治疗作用。本课题将拓展UHRF1生理学功能新认识，并为临床治疗FSGS提供新的靶点，具有重要理论价值和临床应用价值。