基于TGF-β1/Smads 信号通路研究芒果苷元对尿酸性肾病肾纤维化的影响

Renal fibrosis is recognized as a common pathological feature of hyperuricemic nephropathy. TGF-β1 is well identified as a central mediator in renal fibrosis and is substantially upregulated in the injured kidney on both patients and animal disease models. TGF-β1/Smad signaling plays an important role in renal fibrosis. The drugs for treatment of hyperuricemic nephropathy include hypouricemic agens such as allopurinol and benzbromarone. However, drugs available for treatment of hyperuricemic nephropathy are still limited. Therefore, there is an obvious need for novel agents or therapeutic strategies that could act on the physiological regulation of uric acid levels and prevention of uric acid-related diseases. .In our previous study, we found that norathyriol was able to significantly reduce serum urate levels in hyperuricemic animals, and the hypouricemic action was similar to that of benzbromarone. Recently, it was found that norathyriol markedly improved renal function in experimental hyperuricemic nephropathy. Norathyriol at a dose of 2.0 mg/kg significantly reduced not only serum uric acid (SUA), but also serum creatinine (SCr), serum urea nitrogen (SUN), urinary N-acety-β-D-aminoglucosidase (NAG) and urinary β2-microglobulin (β2-MG). But the mechanisms of protection of norathyriol in hyperuricemic nephropathy are still unclear. In the present study, the effects of norathyriol on renal fibrosis in hyperuricemic nephropathy and the mechanisms associated with TGF-β/Smads signal transduction pathway will be studied in vivo and in vitro, mechanism, aiming at making an evaluation on the feasibility of further development as a novel candidate drug for the treatment of hyperuricemic nephropathy.

肾纤维化是尿酸性肾病的主要病理改变之一，阻止肾纤维化进程是防治尿酸性肾病的重要途径。研究表明TGF-β1通过Smads信号通路参与肾纤维化的多个环节，是最强的纤维化诱导因子，有效干预TGF-β1/Smads信号通路有利于尿酸性肾病的防治。本课题组前期发现芒果苷元显著降低高尿酸血症动物的血尿酸水平，对尿酸性肾病小鼠的肾功能有明显改善作用，2.0 mg/kg即能有效降低肌酐和尿素氮水平，以及尿NAG和β2-MG含量，初步显示出高效的特点，目前已申请国家发明专利（申请号：201610181082.3），但对尿酸性肾病的保护作用机制尚未可知。据此，该课题将进一步研究芒果苷元对尿酸性肾病的肾脏保护作用，从TGF-β1/Smads 通路研究芒果苷元对尿酸性肾病肾纤维化影响的作用机制，在动物、细胞和分子水平诠释其可能的肾脏保护机制，以期能将其研发为治疗尿酸性肾病的候选药物做出可行性评价。

肾纤维化是尿酸性肾病的主要病理改变之一，阻止肾纤维化进程是防治尿酸性肾病的重要途径。研究表明TGF-β1通过Smads信号通路参与肾纤维化的多个环节，是最强的纤维化诱导因子，有效干预TGF-β1/Smads信号通路有利于尿酸性肾病的防治。本课题组前期发现芒果苷元显著降低高尿酸血症动物的血尿酸水平，对尿酸性肾病小鼠的肾功能有明显改善作用，2.0 mg/kg即能有效降低肌酐和尿素氮水平，以及尿NAG和β2-MG含量，初步显示出高效的特点，但其防治尿酸性肾病的具体作用机制尚未可知。据此，该课题将进一步研究芒果苷元对尿酸性肾病的肾脏保护作用，从TGF-β1/Smads 通路研究芒果苷元对尿酸性肾病肾纤维化影响的作用机制。.该项目研究表明：芒果苷元能改善氧嗪酸钾和腺嘌呤诱导的尿酸性肾病大鼠的肾纤维化，其作用机制与影响TGF-β1/Smads信号通路中的活性TGF-β1、 P-Smad2、P-Smad3、Smad4的表达有关。细胞水平研究发现芒果苷元能改善TGF-β1诱导的HK-2细胞损伤，抑制TGF-β1诱导的HK-2细胞迁移和侵袭，下调TGF-β1诱导的HK-2细胞中FN、ColⅠ、ColⅢ、Vimentin和 α-SMA的表达，上调E-cadherin的表达，从而影响TGF-β1诱导的HK-2细胞的EMT，并且芒果苷元能通过下调TGF-β1/Smads信号通路中的活性TGF-β1、TGF-βRⅡ、Smad2、Smad4的表达水平改善TGF-β1诱导的HK-2细胞损伤。该项目在动物、细胞和分子水平诠释了芒果苷元对尿酸性肾病的作用机制，为将其研发为治疗尿酸性肾病的候选药物提供实验数据支撑，做出了可行性评价。