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Abstract: PO2015

Modified Lipoproteins Modulate Renal Lymphatic Vessel Vasodynamics via NKCC1 on Lymphatic Endothelial Cells

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1300 Health Maintenance, Nutrition, and Metabolism

Authors

  • Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Liu, Jing, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Shelton, Elaine L., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Delpire, Eric J., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kon, Valentina, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

In addition to its pivotal role in chloride transporting epithelia, the sodium–potassium–chloride cotransporter 1 (NKCC1) is increasingly recognized as a key modulator of vascular tone. We previously documented NKCC1 expression in renal lymphatic endothelial cells (LECs) of rats and cultured human LECs. Ex vivo we showed that blocking NKCC1 by furosemide caused a dose-dependent dilation in renal lymphatic vessels, decreased amplitude, and decreased frequency of spontaneous contractions. Since lymphatic vessels clear interstitial lipids and kidney injury increases lipid peroxidation products including isolevuglandins (IsoLG) which modify lipoproteins (apoAI), we examined if IsoLG-modified apoAI can affect renal lymphatic vessel contractility through NKCC1.

Methods

Puromycin nephrotoxicity (PAN) was induced in Sprague Dawley rats, while non-injected rats served as controls (Cont). Renal lymphatic vessels were isolated and mounted in a perfusion chamber to assess vasoactivity. The effects of apoAI or IsoLG-apoAI on the NKCC1 signaling pathway were assessed in LECs.

Results

PAN rats had significantly higher renal lymph flow which contained significantly more IsoLG vs Cont. Ex vivo studies showed renal collecting lymphatic vessels from PAN were more dilated vs Cont. Immunostaining revealed NKCC1 expression on LECs that was more prominent in PAN renal lymphatic vessels vs Cont. LECs (prox-1 positive cells) isolated from PAN kidneys also had more NKCC1 gene expression than cells from Cont. In LECs, IsoLG-apoAI increased NKCC1 expression vs apoAI. Similarly, WNK1, OxSR1 and SPAK, upstream activators of NKCC1, were significantly increased in LECs exposed to IsoLG-apoAI vs unmodified apoAI, which was accompanied by increased eNOS expression. Ex vivo renal collecting lymphatic vessels significantly increased diameter, amplitude, and frequency of spontaneous contractions when exposed to IsoLG-apoAI vs with apoAI.

Conclusion

IsoLG-apoAI change renal lymphatic vessel vasodynamics through the WNK1-OxSR1/SPAK-NKCC1 pathway on LECs which we propose is a novel target to improve lymphatic vessel function in kidney disease.

Funding

  • NIDDK Support