马兜铃酸I对糜酶/AngII和Oats的双重调控在其肾间质沉积动力学及纤维化中的作用

马兜铃酸肾病（AAN）是药源性肾间质纤维化的典型案例。有研究指出，马兜铃酸（AA）具有在肾中蓄积和难清除的代谢特征，且其与肾纤维化密切相关，然迄今仍未能揭示何种机制使AA长期蓄积于肾并致纤维化，临床对其束手无策。我们发现，AA主要毒性成分AA-I长期存在于大鼠肾间质，且其可抑制肾小管上皮细胞有机阴离子转运体(Oats)的表达，又可促使肥大细胞株释放糜酶。已知糜酶介导间质中血管紧张素II (AngII) 的生成，且糜酶/AngII与血流和纤维化密切相关。课题认为，AA-I对糜酶/AngII和Oats介导的肾微血流及肾分泌的双重抑制是致其沉积于间质的关键，而沉积AA-I对糜酶/AngII的持续作用是其致不可逆肾纤维化的根本。本研究拟采用肾微透析、离体肾灌流和荧光可视化技术考察AA-I间质沉积动力学机制，通过病理学研究探讨AA-I在肾纤维化中的作用，为AAN及其它药源性肾损伤防治提供新思路。

Aristolochic acid nephropathy (AAN) is typical case of drug-induced renal interstitial fibrosis. Studies have shown that aristolochic acid (AA) has a unique metabolic characteristic of long-term accumulation in the kidney, which is related to renal fibrosis closely . However, it has unknown yet that the mechanism of AA accumulation in the kidney for long-term and how to cause renal fibrosis. Thus clinical treatment is lack. Our research found that AA-I, the main toxic component of AA, inhibited the expression of organic anion transporters (Oats) in renal tubular epithelial cells. In addition, AA-I existed in rat renal interstitium for a long time, and it could stimulate line of mast cells to release chymase. Chymase is known to mediate production of angiotensin II (AngII) in the renal interstitium mainly, and Chymase/AngII is closely related to both renal interstitial microcirculation and fibrosis. Thus, we hypothesize that the dual inhibition of AA-I on chymase/AngII and OATs could be the key to the deposition of AA-I in renal interstitium. Furthermore, the sustained effect of AA-I accumulated in renal interstitial on chymase/AngII could be the primary cause of irreversible interstitial fibrosis. In this work, renal microdialysis, in vitro renal perfusion and fluorescence visualization will be used to investigate the mechanism of interstitial deposition pharmacokinetics of AA-I. Renal fibrosis induced by AA-I will be evaluated by pathology. This project would provide a new idea for the prevention and treatment of AAN or other drug-induced renal injuries.