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

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $721,712

## Abstract

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.

## Key facts

- **NIH application ID:** 10854821
- **Project number:** 5R01DK135764-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** VALENTINA KON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $721,712
- **Award type:** 5
- **Project period:** 2023-06-02 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854821

## Citation

> US National Institutes of Health, RePORTER application 10854821, Salt Mediated Cross Talk Between Lymphatic Vessels and Immune Cells in Kidney Disease (5R01DK135764-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10854821. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*