Abstract: TH-OR28
Renal Lymphatic Pumping Involves Interstitial Sodium Regulation of NKCC1 Transporter
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic and Clinical Research
November 04, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Fluid, Electrolyte, and Acid-Base Disorders
- 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Liu, Jing, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Zhong, Jianyong, 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
Sodium-potassium-chloride cotransporter 1 (NKCC1) is regulated by extracellular sodium and has recently been shown to modulate vascular dynamics contributing to hypertension. Previously, we showed that NKCC1 is expressed in renal lymphatic vessels of rats and in cultured human lymphatic endothelial cells (LECs). Since interstitial sodium retention is a hallmark of proteinuric injury and nephrotic syndrome, we examined whether high interstitial sodium environment affects expression of the NKCC1 transporter and alters pumping dynamic function of renal lymphatic vessels.
Methods
Puromycin aminonucleoside injected rats (PAN) served as a model of nephrotic syndrome and saline-injected rats served as control. In vivo, MRI was used to assess the renal sodium and water content. Renal lymph, which reflects the interstitial composition, was collected and sodium concentration analyzed. Ex vivo, contractile dynamics of isolated renal collection lymphatic vessels were studied in a perfusion chamber. Cultured LECs were used to assess the effects of high sodium on NKCC1.
Results
MRI revealed a significant elevation in the renal sodium and water content in PAN vs control rats. The renal lymph of PAN contained significantly higher sodium vs controls although the plasma sodium concentration was not different between the groups. Ex vivo studies revealed that high sodium environment decreased contractility of renal collecting lymphatic vessels. Immunostaining and PCR studies showed PAN injury increased NKCC1 expression in renal lymphatic vessels vs control. In cultured LECs, high sodium concentration increased mRNA and reduced phosphorylated NKCC1 protein as well as SPAK, an upstream activating kinase of NKCC1, and eNOS, a downstream link between LECs and smooth muscle cells. Like high sodium environment, furosemide, an NKCC1 inhibitor, showed a weaker effect on amplitude and ejection fraction in isolated renal lymphatics of PAN vs controls.
Conclusion
High sodium within the renal interstitium following proteinuric injury impairs the pumping function of renal lymphatic vessels through SPAK-NKCC1-eNOS pathway that may contribute to sodium and water retention and reduces lymphatic responsiveness to furosemide. We propose this dysfunctional pathway in lymphatic vessels is a novel mechanism of progressive edema in proteinuric kidney disease.
Funding
- NIDDK Support