草酸盐转运体SLC26A6在特发性草酸钙结石发病中的作用研究

Most of urinary calculus is calcium oxalate stone, the oxalate is excreted mainly in the urine, and the oxalate concentration is restricted in specific range to avoid hyperoxaluria and stone forming by kidney. This physiological function is conducted by SLC26A family, SLC26A6, a member of the family is the most predominant effector. SLC26A6-null mice had significant hyperoxaluria and higher oxalate concentration in blood, the incidence of calcium oxalate stone was also obviously increased. Idiopathic hyperoxaluria (IH) is the most common hyperoxaluria, it is considered to be related to some gene dysfunction involved in oxalate transporting. Our preliminary research found that the expression of SLC26A6 was lower in IH patients than in the controls. So we set up the hypothesis that SLC26A6 involves in the pathogenesis of IH. In this study, we plan to study the expression, gene mutation of SLC26A6 in IH rats and IH patients, investigate the possibility of reducing the incidence of urinary calcium oxalate stone by up-regulating SLC26A6. This work will provide new molecular therapeutic target and theoretical basis for the prevention and treatment of IH and urinary calcium oxalate stone.

高草酸尿是草酸钙结石最重要的成石因素。近年来研究发现，草酸的吸收和分泌主要通过阴离子转运体SLC26A家族介导的跨膜转运来实现，其中以SLC26A6最重要。草酸的转运异常被认为是特发性高草酸尿(IH)形成的重要原因，但详细机制一直未明。最新研究显示SLC26A6基因敲除小鼠血、尿草酸升高，草酸钙尿石症发生率也明显升高；我们前期研究也发现草酸钙尿石症患者肾脏中SLC26A6表达较正常对照组降低。据此我们推测： SLC26A6可能是IH及草酸钙结石发病的一个分子靶点。本课题将通过研究SLC26A6在IH大鼠、IH患者体内的表达水平，以及IH患者SLC26A6基因的变异情况，明确SLC26A6是否参与了特发性草酸钙结石的发病；并上调IH大鼠以及实验性草酸钙结石大鼠体内SLC26A6的表达，观察是否能降低尿液草酸浓度及减少结石的发生，为特发性草酸钙结石的防治提供新的分子靶点和理论依据。

高草酸尿是特发性草酸钙结石的独立危险因素，草酸在体内的转运异常是导致高草酸尿的危险因素。SLC26A6是重要的草酸转运离子，主要分布于肠道和肾脏中，介导草酸由体内到体外的分泌以及体外至体内的吸收。本研究重点关注肾脏内SLC26A6对于体内草酸的转运作用研究。通过对于特发性结石患者和非结石患者的肾脏进行研究，我们发现特发性草酸钙结石患者肾脏内SLC26A6表达较一般非结石患者更高。随后，我们利用慢病毒技术转染大鼠肾脏，使其分别高表达和低表达Slc26a6，发现大鼠肾脏内Slc26a6表达升高后尿草酸升高，更容易产生结石；相反，下调Slc26a6能起到一定保护性作用。利用miRNA芯片检测分析高草酸尿大鼠和正常大鼠肾脏内miRNA表达谱差异，发现28个差异显著的miRNA。