炎症加重脂质介导的内质网应激在儿童原发肾病综合征足细胞损害中的分子机制

Primary nephrotic syndrome (PNS) is the most important etiology of children with chronic renal function failure in China, Minimal change nephrotic syndrome(MCNS) which characterized by podocyte foot processes show effacement and fusion has a good prognosis, while focal segmental glomerulosclerosis(FSGS) which characterized by podocyte apoptosis has a bad prognosis. A preliminary study of our group have confirmed (NSFC: 30672267): inflammation leads to lipid accumulation in the kidney through disruption the feedback regulatory loop of low-density lipoprotein receptor (LDLr), the upregluation of LDLr express is a main pathway of lipid accumulation wihtin podocytes and (or) mesangial cells in the kidney，and then induced foam cell formation, which will further aggravated kidney injury. Combined with our present study, we propose the hypothesis that cooperation of CD36 molecule, a intracellular cholesterol or fatty acids transporter, which will induce or accelerate lipids once again accumulates into the endoplasmic reticulu under inflammatiom stress conditions. This event will perturbations of ER homeostasis affect protein folding and cause endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR)-CHOP pathway, eventually lead to podocytes apoptosis, which play an important role in kidney injury and even contributes to progression to FSGS..In this study using mice model with adriamycin nephropathy、podocyte and renal biopsy specimens of PNS in the children, we will show that inflammatory stress exacerbates lipid-mediated ER stress which lead to podocytes apoptosis through LDLr/CD36-UPR-CHOP pathway. It will provide an opportunity to exploit a novel preventive and therapeutic strategies for podocyte injury and glomerulosclerosis in an early stage.

原发性肾病综合征（PNS）是我国儿童慢性肾功能衰竭的重要病因，以足细胞足突融合为主要病理表现的肾小球微小病变（MCNS）预后良好，而以足细胞凋亡为主要病理表现的局灶节段性肾小球硬化（FSGS）预后差；本课题组前期研究证实（NSFC：30672267）：LDLr上调是炎症加重脂质向肾脏足细胞、系膜细胞聚集，诱导泡沫样细胞形成的主要途径；结合现有研究，我们提出：儿童PNS，炎症应激下肾脏足细胞LDLr上调、脂质摄取异常增多，在CD36协同下，胞内脂质将再次向内质网异常聚集而致内质网应激，继而启动CHOP信号通路，促进肾小球足细胞凋亡、细胞数量减少！这可能是诱导MCNS肾脏病理损伤加重并向FSGS发展的重要分子机制，本项目拟用足细胞系、阿霉素肾病鼠及PNS肾组织进行体内、体外实验，以新的视角阐明儿童PNS的发病机制，为早期防治足细胞损害、肾小球硬化，进而为改善预后提供新的干预靶点及治疗手段。

原发性肾病综合征（PNS）是我国儿童慢性肾功能衰竭的重要病因，以足细胞足突融合为主要病理表现的肾小球微小病变（MCNS）预后良好，而以足细胞凋亡为主要病理表现的局灶节段性肾小球硬化（FSGS）预后差；本课题组前期研究已证实（NSFC：30672267）：LDLr 上调是炎症加重脂质向肾脏足细胞、系膜细胞异常沉积，进而诱导泡沫样细胞形成、肾小球硬化的途径之一；结合现有研究基础，我们提出科学假说：儿童 PNS，炎症应激下肾脏足细胞 LDLr 上调、脂质摄取异常增多，在 CD36 协同下，胞内脂质将再次向内质网异常聚集而致内质网应激（ERS），继而启动 CHOP 信号通路，促进肾小球足细胞凋亡、细胞数量减少，这可能是诱导MCNS 肾脏病理损伤加重并向 FSGS 发展的重要分子机制。. 本项目采用人系膜细胞系、小鼠足细胞系及嘌呤霉素肾病鼠进行体内外实验，得到以下结论：1、炎症可加重高脂介导的系膜细胞及足细胞脂质沉积，ERS发生，从而导致足细胞凋亡、系膜细胞增殖及系膜基质生成增多，而CHOP信号通路在此过程中发挥重要作用；2、通过干预内质网应激信号（阻断或预处理内质网应激）可减轻足细胞及系膜细胞内脂质沉积、减少凋亡；3、炎症可加重嘌呤霉素肾病鼠的血脂、尿蛋白及肾脏病理学改变，阻断内质网应激可能使这些改变有效减轻；4、炎症状态下，足细胞、系膜细胞内NPC1正常生理调控失调，促进异常沉积胆固醇定向内质网转运聚集，从而介导ERS发生，而通过干预NPC1，可有效缓解ERS。.综上所述，本项目研究发现在炎症状态下，胆固醇可异常向足细胞、膜膜细胞细胞内沉积，进而通过NPC1途径进而向内质网聚集，介导ERS发生，对肾脏足细胞及系膜细胞的损害，这可能是诱导MCNS肾脏病理损伤加重并向FSGS发展的重要分子机制；而通过干预ERS或NPC1途径，可能部分缓解儿童PNS肾脏损害，进而为临床延缓至肾小球硬化提供新的干预靶点与治疗手段。.