circRSPRY1靶向miR-21/PTEN信号轴在草酸钙结晶诱导肾小管上皮细胞坏死性凋亡的作用及机制研究

草酸钙结石为最常见的肾结石，其复发率高且发病机制不明，如何防治是临床亟待解决的问题。研究发现，草酸钙结晶诱导肾小管上皮细胞坏死性凋亡是促进结石粘附聚集的关键因素，但具体调控机制不清。我们预实验发现：circRSPRY1在小鼠和细胞肾结晶模型中表达降低，过表达circRSPRY1可抑制草酸钙结晶诱导的肾小管上皮细胞坏死性凋亡，且PTEN表达升高；生物信息学预测circRSPRY1序列上有miR-21的结合位点。我们推测：草酸钙结晶通过抑制肾小管上皮细胞表达circRSPRY1导致其对miR-21的海绵效应减弱，从而抑制PTEN表达，增强细胞坏死性凋亡，促进草酸钙结石的发生。本项目拟从整体和细胞水平探究circRSPRY1靶向miR-21/PTEN调控草酸钙结晶诱导肾小管上皮细胞坏死性凋亡的机制，从而为circRSPRY1成为肾草酸钙结石特异性诊断标志物和防治靶点提供新思路。

Calcium oxalate stones is the most common kidney stones, which has high recurrence rate and its pathogenetic mechanisms remain obscured. Hence, to find an effective prevention and treatment strategy is an urgent issue for clinicians. Recent stundies indicate necroptosis of renal tubular epithelial cells induced by calcium oxalate crystals is a key factor in promoting stone crystals adhesion and aggregation, but little is known about the specific regulatory mechanisms. In our pilot tests, circRSPRY1 expressions significantly decreased in vivo and in vitro renal crystal models. Overexpressing of circRSPRY1 in renal tubular epithelial cells inhibited necroptosis induced by calcium oxalate crystals, and increased expression of PTEN. Predicting results obtained by bioinformatics indicates circRSPRY1 has binding site of miR-21. We speculate that in the process of renal calcium oxalate stones occurrence, low expression of circRSPRY1 may lead to a reduction sponge effect on miR-21 so as to suppress PTEN expression, thereby enhance renal tubular epithelial cells necroptosis, and finally facilitate formation of calcium oxalate stones. Our project intend to investigate the role and mechanism of circRSPRY1 / miR-21 / PTEN axis in regulating necroptosis of renal tubular epithelial cells induced by calcium oxalate crystals in vivo and in vitro, Meanwhile, we hope to provide new ideas and scientific basis for circRSPRY1 as a specific diagnostic marker as well as preventable and therapeutic vector for kidney calcium oxalate stones.