抑制自噬-溶酶体通路对狼疮性肾炎状态下肾小管损伤及抗损伤能力的影响

近年来，几大权威肾病治疗指南均建议将具有联合抑制自噬活性和溶酶体功能的抗疟药作为狼疮性肾炎（LN）治疗的基础用药。但我们研究发现：蛋白尿在导致肾小管上皮细胞（TECs）损伤同时，其溶酶体膜受损且消化功能下降,而自噬活化则是TECs为减轻尿蛋白对自身损伤所起的一种保护性反应。因此我们推测，应用抗疟药抑制自噬-溶酶体通路可能会导致大量蛋白尿LN患者肾小管损伤或抗损伤能力下降。为验证上述假设，本项目拟在已发现自噬抑制可加剧尿蛋白对TECs损伤的基础上，首先采用体外研究探讨抗疟药是否会削弱TECs抗损伤能力，而联合应用皮质激素（溶酶体膜稳定剂和自噬促进剂）能否抵消上述效应；继之采用LN小鼠模型，探讨抗疟药对免疫炎症及蛋白尿双重因素所致肾小管损伤的影响，以及其对狼疮小鼠抵抗继发性急性肾损伤能力的影响，并进一步研究联合应用激素后，上述效应的变化；最后在临床LN患者上进一步验证上述假设。

Recently, several important guidelines for kidney disease treatment recommended that antimalarial, a inhibitor of autophagic-lysosomal pathway, should be administrated in patients with lupus nephritis (LN). However, our previous studies found that lysosomes were ruptured during tubular epithelial cell (TEC) injury induced by continuous excess proteinuria，while autophagy activation mounted an adaptive response in TECs after urinary protein overload. Therefore, we hypothesize that clinical application of antimalarial, through inhibiting autophagic-lysosomal pathway, may aggravate renal tubular injury and/or suppress the adaptive response during kidney injury in LN patients with heavier proteinuria. In the present study, since we have found that chloroquine could aggravate TECs injury induced by urine proteins, we firstly study whether chloroquine (an antimalarial) weakens the resistance of TEC to the stress and injury, as well as demonstrat whether corticosteroids counteract the action of chloroquine. Secondly, we investigate the effects of hydroxychloroquine on the injury and ability of resisting injury/stress during double setback of immune inflammation and urinary proteins in mice with LN and excess proteinuria. Also, whether corticosteroids counteract the actions of hydroxychloroquine is also investigated in LN mouse. Finallry, our hypothese will be further validated in LN patients with excess proteinuria.