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

盐介导肾脏疾病中淋巴管和免疫细胞之间的交互作用

• 批准号: 10636755
• 负责人: VALENTINA KON
• 金额: $ 76万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-02 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636755
• 关键词: Acceleration; Adoptive Transfer; Affect; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apolipoprotein A-I; Biological; Blood Vessels; Calcium; Cell Communication; Cell physiology; Cells; Cholesterol; Chronic Kidney Failure; Coronary heart disease; Cultured Cells; Data; Disease; Elements; Endothelial Cells; Endothelin; Endothelin-1; Endothelin-3; Environment; Fibrosis; Fluid Balance; Growth; Human; Immune; Impairment; In Vitro; Inflammation; Inflammation Mediators; Injury; Injury to Kidney; Intercellular Fluid; Kidney; Kidney Diseases; Ligands; Link; Lipids; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Lymphocyte; Mannitol; Mediating; Mus; NADP; Oxidases; Oxidative Stress; Pathway interactions; Population; Proteins; Publishing; Renal function; Role; Skin; Sodium; Sodium Chloride; Sodium-Potassium-Chloride Symporters; Structure; T-Cell Activation; Testing; Time; Tissues; Treatment Efficacy; Vascular Diseases; Water; adaptive immune response; adduct; blood pressure elevation; chemokine; comorbidity; conditional knockout; constriction; cytokine; epithelial Na+ channel; humanized mouse; hypertensive; immune activation; immune cell infiltrate; immune clearance; immunoregulation; in vivo; interstitial; kidney fibrosis; lymphatic circulation; lymphatic dysfunction; lymphatic pump; lymphatic vessel; macromolecule; monocyte; mouse model; mutant; neoantigens; nephrotoxicity; novel; oxidation; promoter; receptor; recruit; renal damage; response; trafficking; uptake; urinary; vasoconstriction

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.

概括 淋巴血管对于维持间质液体稳态，免疫细胞运输和抗原至关重要 清除。由于淋巴运输不足而导致的无效清除是许多疾病的关键启动子， 反映了淋巴血管网络的数量不足，重吸收能力和收缩力。相比之下 对于血管，淋巴管对间质元素非常敏感，包括Na+ 高血压环境中淋巴生长的强大调节剂。我们在高血压环境中的研究发现 Na+激活了高反应性脂质氧化产物，抗原呈现免疫的抗原中的异戊瓜素（ISLEG） 细胞（APC）通过上皮Na+通道（ENAC）。我们的新数据显示蛋白尿肾脏疾病增加 肾内Na+，从而在肾脏实质中建立高Na+环境。喜欢免疫中的enac 细胞，Na+，而不是渗透压，调节氯化钠共转运蛋白（NKCC1）的表达 淋巴内皮细胞（LEC）。蛋白尿动物以及人类的尿菌株水平升高 加入到载脂蛋白AI（ApoAI）中，以其在炎症，氧化应激和胆固醇中的作用而闻名 处理动脉粥样硬化心脏病。尽管肾脏疾病表现出与修改的所有合并症 Apoai，对这些对肾脏的影响一无所知。我们首次表明肾脏损伤促进 肾内分离室和隔离apoai上调了LEC中的NKCC1。一起，我们出版的和初步 数据支持肾脏损伤导致肾脏Na+积累的假设 淋巴管生成，激活LEC，削弱淋巴动力学，鼓励免疫细胞 通过涉及通过NKCC1和ISLEG进行Na+传感的机制运输到肾脏间质中 LECS的吸收。我们的研究将定义肾内Na+积累如何调节淋巴网络和 肾脏淋巴管和激活的免疫细胞之间的串扰，我们假设促进间质停滞 潜在有害的分子和细胞以及随后的肾小管间隙纤维化。为了检验这一假设，我们 提出三个机械目标。 AIM 1将检验以下假设：肾脏在肾脏中损伤驱动的积累 间质直接通过Iselg-nkcc1直接破坏肾脏淋巴网络的结构和功能 路径。 AIM 2将定义Na+活化的免疫细胞如何涉及分离和血管收缩的内皮素至 损害肾脏淋巴管，从而增加肾脏间质停滞。在AIM 3中，我们将确定激活 来自CKD钝性淋巴管生成的人的单核细胞具有高分离的单核细胞，淋巴泵送弱 这促进了人性化小鼠的进行性肾脏纤维化。