黄芪甲苷调控Th17和Treg细胞分化防治肾损伤的机制研究

Struggle between vital qi and pathogenic factor runs through the course of the development and progression of kidney injury. Astragaloside IV can strengthen the body resistance to eliminate pathogenic factor and prevent kidney injury. Kidney injury molecule-1(KIM-1) participates in the onset of kidney injury partially by binding to the receptor named L-selectin on CD4+ T-lymphocyte specificly. Preliminary study confirmed that high expression of KIM-1 accompanied T-lymphocyte infiltration, and astragloside IV could improve kidney injury through reducing both KIM-1 expression and T-lymphocyte infiltration. But the specific mechanism of astragaloside IV preventing kidney injury remains to be explored. Therefore, we propose a hypothesis: KIM-1promotes differentiation from CD4+T lymphocytes to Th17 cell through L-selectin, inhibits Treg cells, boosts the immune inflammatory response, and induces kidney injury, which is namely that vital is insufficient and pathogenic factor is excessive, so chronic disease enters into fibrosis procedure; while astragaloside IV can inhibit KIM-1 expression, block its function of regulating CD4+ T-lymphocyte differentiation, thus eliminate pathogenic factors and achieve recovery through improving immune inflammatory response and promoting kidney repair. In this study, we adopt immunity recovery in vivo and primary cultures in vitro to identify the role of Th17 and Treg in renal injury, explore mechanism of KIM-1 mediating kidney immune inflammatory response through regulating balance of Th17 and Treg cells, and clarify new perspectives of astragaloside IV preventing kidney injury. This study will help to understand the cellular and molecular mechanisms involved the prevention of renal injury through astragaloside IV therapy and provide important insights in the development of Chinese herb.

正邪相争贯穿肾损伤过程，黄芪甲苷（AS-IV）能扶正祛邪，防治肾损伤。肾损伤分子-1（KIM-1）参与肾损伤，CD4+T淋巴细胞表达的L-选择素是其受体。前期发现，KIM-1表达区域伴T淋巴细胞浸润，AS-IV能抑制KIM-1表达，减少T淋巴细胞浸润。但AS-IV调控免疫防治肾损伤的机制不清。故推测：KIM-1通过L-选择素促进CD4+T淋巴细胞向Th17分化，抑制Treg产生，促进炎症，加重肾损伤，即正虚邪实，久病入络；而AS-IV通过益气通络抑制KIM-1表达、阻断KIM-1对Th17和Treg的调控，改善炎症，促进修复，实现正胜邪退、病情痊愈。项目旨在活体动物和体外原代培养的基础上，采用免疫构建方法，研究Th17和Treg在肾损伤中的作用，探索KIM-1调控Th17和Treg分化介导肾脏免疫反应的机制，揭示AS-IV防治肾损伤的新机理。预期结果有助于理解AS-IV的新作用靶点。

KIM-1是肾损伤早期标记物，前期研究发现，在肾纤维化动物模型受损肾小管中KIM -1表达局部伴T淋巴细胞浸润;以黄芪甲苷(AS-IV)的益气通络作用能够抑制KIM-1表达，可改善肾纤维化。本研究通过体内和体外实验探讨AS-IV防治急性肾损伤和肾纤维化的具体机制。研究结果明确肾损伤过程，肾小管上皮细胞表达KIM-1，KIM-1能够与CD4+T淋巴细胞表面的 L-选择素相互作用，促进Th17细胞分化，抑制Treg细胞产生，引起Th17和Treg细胞失衡，促进炎症反应，加重肾损伤; 黄芪甲苷能够抑制KIM-1表达，阻断Th17/Treg细胞失衡，发挥抗炎作用，促进肾损伤恢复。本研究发现KIM-1对Th17和Treg细胞分化的调控作用，探讨了黄芪甲苷防治肾损伤的新机理，有助于进一步挖掘黄芪的临床应用价值。

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