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

总结

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.