Salt Mediated Cross Talk Between Lymphatic Vessels and Immune Cells in Kidney Disease

摘要 淋巴管对于维持间质液体的稳态、免疫细胞的运输和抗原是必不可少的。 通行证。由于淋巴运输不足而导致的清除不力是许多疾病的关键促进剂 反映淋巴管网的数量、再吸收能力和收缩能力不足。相比之下， 对于血管，淋巴管对间质元素非常敏感，包括Na+，这是一种 高血压环境下淋巴生长的强大调节器。我们在高血压环境中的研究发现 Na+在抗原提呈免疫中激活高活性脂氧化产物异紫球蛋白(IsoLG) 细胞(APC)通过上皮性钠离子通道(ENaC)。我们的新数据显示蛋白尿肾病增加 肾脏内的Na+，从而在肾实质内建立高Na+的环境。就像免疫中的ENaC Na+，而不是渗透压，调节钠钾协同转运体(NKCC1)的表达 淋巴管内皮细胞。与人类一样，蛋白尿动物的尿液IsoLG水平也升高 加成物载脂蛋白AI(ApoAI)，因其在炎症、氧化应激和胆固醇中的作用而闻名 动脉粥样硬化性心脏病的处理。虽然肾脏疾病表现为所有与改良的 ApoAI，关于这些对肾脏的影响，人们知之甚少。我们第一次展示了肾脏损伤促进 肾内IsoLG和IsoLG-ApoAI上调晶状体上皮细胞NKCC1表达总而言之，我们的出版和初步 数据支持这样一种假设，即肾脏损伤导致肾脏Na+积聚，从而刺激 淋巴管生成，激活LECs，削弱鼓励免疫细胞的淋巴动力学 NKCC1和IsoLG参与Na+感受的肾间质转运机制 被LECs摄取。我们的研究将定义肾内Na+积聚如何调节淋巴网络和 肾淋巴管和激活的免疫细胞之间的串扰，我们假设会促进间质停滞 潜在的有害分子和细胞以及随后的肾小管间质纤维化。为了检验这一假设，我们 提出三个机械论目标。目标1将检验这样一种假设，即损伤导致的肾脏Na+积累 间质通过IsoLG-NKCC1直接破坏肾淋巴网络的结构和功能 路径。AIM 2将定义Na+激活的免疫细胞如何参与IsoLG和血管收缩内皮素以 损害肾淋巴管，从而增加肾间质停滞。在目标3中，我们将确定激活的 CKD患者高IsoLG单核细胞淋巴管生成迟钝，淋巴泵功能减弱 这促进了人源化小鼠的进行性肾脏纤维化。

SUMMARY Lymphatic vessels are essential to maintaining interstitial fluid homeostasis, immune cell trafficking and antigen clearance. Ineffectual clearance due to inadequate lymphatic transport is a key promoter of many diseases that reflects insufficient number, reabsorptive capacity and contractility of the lymphatic vascular network. In contrast to blood vessels, lymphatic vessels are exquisitely sensitive to interstitial elements, including Na+ which is a powerful regulator of lymphatic growth in hypertensive settings. Our studies in hypertensive settings, have found Na+ activates the highly reactive lipid oxidation product, isolevuglandin (IsoLG) in antigen presenting immune cells (APCs) via the epithelial Na+ channel (ENaC). Our new data reveal proteinuric kidney disease increases intrarenal Na+ and thus establish a high Na+ environment within the kidney parenchyma. Like ENaC in immune cells, Na+, not osmolality, modulates expression of the sodium potassium chloride co-transporter (NKCC1) in lymphatic endothelial cells (LECs). Proteinuric animals as well as humans have elevated levels of urinary IsoLG adducted to apolipoprotein AI (apoAI) best known for its role in inflammation, oxidative stress, and cholesterol handling in atherosclerotic heart disease. Although kidney disease manifests all co-morbidities linked to modified apoAI, little is understood about these effects on kidneys. We show for the first time that kidney injury promotes intrarenal IsoLG and that IsoLG-apoAI upregulates NKCC1 in LECs. Together, our published and preliminary data support the hypothesis that kidney injury leads to renal Na+ accumulation which stimulates lymphangiogenesis, activates LECs, weakens lymphatic dynamics that encourages immune cell trafficking into the renal interstitium through mechanisms that involve Na+ sensing via NKCC1 and IsoLG uptake by LECs. Our studies will define how intrarenal Na+ accumulation modulates the lymphatic network and crosstalk between renal lymphatics and activated immune cells which we postulate promote interstitial stagnation of potentially harmful molecules and cells and subsequent tubulointerstitial fibrosis. To test this hypothesis, we propose three mechanistic aims. Aim 1 will test the hypothesis that that injury-driven accumulation of Na+ in renal interstitium directly disrupts the structure and function of the renal lymphatic network via a IsoLG-NKCC1 pathway. Aim 2 will define how Na+ activated immune cells involve IsoLG and vasoconstricting endothelins to impair renal lymphatics thereby increasing renal interstitial stagnation. In Aim 3 we will determine that activated monocytes with high IsoLG from humans with CKD blunt lymphangiogenesis and weaken lymphatic pumping that promotes progressive kidney fibrosis in humanized mice.