蛋白尿诱导的肾小管分泌功能异常：肾脏病水盐失衡的新机制

In kidney disease patients, particularly in the patients with nephrotic syndrome, the disorder of fluid metabolism is a common clinical phenomenon, resulting in the edema and hypertension. Many patients with nephritic syndrome are resistant to loop diuretics and anti-hypertensive drugs. The incomplete understanding on the pathogenic mechanisms of kidney disease-related fluid imbalance makes it difficult to be dealt with in clinic. In our preliminary studies, we found that in proteinuric patients and albumin-overloaded mice, upregulation of NLRP3, COX-2, and mPGES-1 in kidney might contribute to the downregulation of NKCC2, while a stimulation of Ang II could lead to the upregulation of NHE3 and NCC, which are related to a downregulation of MnSOD. Then we hypothesized that proteinuria, a common feature of kidney diseases serves as a key intra-renal factor in resetting renal salt handling. Based on our preliminary data and previous reports, we will define: 1) albuminuria-induced mitochondrial oxidative stress activate NLRP3 inflammasome/COX-2/mPGES-1/PGE2 signaling in TAL (thick ascending limb) to downregulate NKCC2 expression, leading to the resistance to loop diuretics; 2) in PT (proximal tubule) and DCT (distal convoluted tubule), albuminuria-induced mitochondrial oxidative stress stimulate RAS to enhance NHE3 and NCC, leading to the fluid retention, edema, and hypertension. In this proposal, we will fully investigate the pathological role of albuminuria in resetting renal salt handling and the underlying mechanisms via using conditional gene KO mice (NLRP3, COX-2, mPGES-1, and AT1) and pharmacological strategies inhibiting mitochondrial oxidative stress and RAS in vivo and in vitro. This study will offer novel targets for the treatment of kidney disease-associated imbalance of salt and water metabolism.

肾病患者的水盐代谢失衡及水肿和高血压是常见的临床现象，且多伴有一定程度的襻利尿剂抵抗，具体机制尚不清楚。基于蛋白尿是肾脏疾病的普遍现象，我们推测蛋白尿可能是介导水盐代谢紊乱的关键肾内因素。在蛋白尿患者及白蛋白负荷小鼠肾脏，我们发现在MnSOD下降的同时，NLRP3、COX-2、mPGES-1增高与NKCC2下降相关；而Ang II的增加与NHE3和NCC上调相关；补充MnSOD显著改善了盐通道及相关信号蛋白的表达异常。据此提出：蛋白尿在髓攀通过线粒体ROS激活NLRP3炎症小体/COX-2/mPGES-1/PGE2 通路，介导NKCC2的下调和对襻利尿剂的抵抗；在近/远曲小管，蛋白尿通过线粒体ROS/ Ang II上调NHE3和NCC表达，增加水钠重吸收。本课题应用条件性基因敲除小鼠及药物阻断线粒体氧化应激和RAS等，研究蛋白尿调节肾脏水盐代谢的作用及机制，为干预肾脏病体液失衡提供新视点。

蛋白尿是各类肾脏疾病中最常见的临床表现之一。在临床上，蛋白尿不仅仅是慢性肾脏疾病（CKD）的临床诊断指标，也参与了肾小管损伤及肾功能障碍进展。在各类CKD，水盐代谢及血压稳态失衡是患者的常见临床表现，但是具体机制尚不清楚。本项目在蛋白尿模型通过研究NLRP3炎症小体、COX-2/mPGES-1/PGE2通路、RAS系统及氧化应激的相互作用关系，阐明了： 1. NLRP3炎症小体活化在白蛋白尿诱导的NKCC2下调及功能变化中的作用；2.COX-2/mPGES-1/PGE2通路活化在白蛋白尿诱导的NKCC2下调及功能变化中的作用；3. Ang II 在白蛋白诱导的NHE3和NCC上调中的作用；4 线粒体氧化应激在白蛋白尿诱导的盐通道表达和功能异常及相关信号通路活化中的作用。系列研究与结果不但为深入理解CKD相关的水盐代谢及血压稳态失衡提供了新见解，也为临床干预CKD水盐代谢紊乱及肾性高血压提供了新思路。

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