肾小管源性PCSK9在肾病综合征相关高胆固醇血症中的作用探讨

The pathogenesis of nephrotic syndrome (NS)-related dyslipidemia remains unclear. In addition to the liver, whether kidney, as an important endocrine organ, is directly involved in that pathogenesis is worth investigating. Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is closely related to lipid metabolism, such as hypercholesteremia. Our previous research have found that the protein level of plasma PCSK9 of NS patients was elevated, and the renal biopsy immunohistochemical staining also showed that the protein level of PCSK9 in tubular was elevated. Moreover, the cellular research verified that urine protein of NS patients could upregulate the level of PCSK9 in renal tubular epithelial cells by a dose-dependent manner. As mentioned in other research, the urinary protein could induce endoplasmic reticulum stress in renal tubular epithelial cells and endoplasmic reticulum stress could upregulate expression level of SREBP-2 and inhibits expression level of Sortilin, affecting the expression and secretion of PCSK9. Since we have also observed that renal tubular epithelial cells could express SREBP-2 and Sortilin in our previous study, we could speculated that urinary protein could upregulate of SREBP-2 and inhibit of Sortilin through the induction of endoplasmic reticulum stress in renal tubular epithelial cells, thereby promoting the expression and secretion of PCSK9 and leading to hypercholesterolemia. In this study, tubular-specific PCSK9 knockout mice were used as models to investigate the effects of renal tubular-derived PCSK9 on NS-related hypercholesterolemia, and we also aims to investigating the mechanism of urinary protein regulating PCSK9 in renal tubular epithelial cells.

肾病综合征的高胆固醇血症机制不清，除肝脏外，肾脏作为重要内分泌器官是否参与其发生值得探讨。PCSK9与高胆固醇密切相关。我们前期观察发现肾病综合征患者血浆PCSK9升高，同时肾活检免疫组化发现患者肾小管PCSK9表达增加，且细胞实验证实尿蛋白可呈剂量依赖性上调近端肾小管上皮细胞PCSK9。此外，我们还发现近端肾小管上皮细胞表达SREBP-2和Sortilin，且Sortilin可能与PCSK9分泌有关。结合他人研究发现尿蛋白可诱导肾小管上皮细胞内质网应激，我们推测：尿蛋白通过诱导肾小管上皮细胞内质网应激，经SREBP-2和Sortilin途径分别促进PCSK9表达和分泌，进而升高循环PCSK9水平导致高胆固醇血症。本研究将采用近端肾小管PCSK9特异性敲除小鼠为模型，探讨肾小管源性PCSK9对肾综相关高胆固醇血症的影响，并以近端肾小管上皮细胞为对象，探讨尿蛋白调节PCSK9的机制。

较高水平的低密度脂蛋白能够加速动脉粥样硬化进程，而前蛋白转化酶枯草杆菌蛋白酶/kexin-9 (PCSK9) 通过控制细胞膜膜上的 LDL 受体表达间接调节血浆 LDL 水平，也因此被认为是参与动脉粥样硬化进程的重要位点之一。肾病综合征常常伴有明显的高胆固醇血症，我们在前期研究中发现肾病综合征患者血浆PCSK9升高，同时肾活检免疫组化发现患者肾小管PCSK9表达增加，且细胞实验证实尿蛋白可呈剂量依赖性上调近端肾小管上皮细胞PCSK9。在近端肾小管上皮细胞中我们发现了SREBP-2和Sortilin的表达，且Sortilin的表达水平与血清PCSK9水平呈显著正相关，提示Sortilin可能通过PCSK9对肾病综合征患者的血脂代谢紊乱产生影响。不仅如此，临床研究中我们还发现了血清PCSK9水平与血小板反应性之间的相关性，观察到了餐后低密度脂蛋白胆固醇、PCSK9以及富含甘油三酯的胆固醇值水平的显著性改变，以及餐后数小时LDL-c胆固醇的重分配现象。在基础研究中，我们发现二甲双胍能够通过ChREBP介导PCSK9水平的调控，揭示了二甲双胍降低胆固醇的新作用机制，以及细胞内葡萄糖和胆固醇稳态之间的相互调控方式。综上所述，我们的研究进一步为深入理解PCSK9对于血脂调控的作用机制提供了新思路。