Abstract
Lymphatic vessels are highly responsive to changes in the interstitial environment. Previously, we showed renal lymphatics express the Na-K-2Cl cotransporter. Since interstitial sodium retention is a hallmark of proteinuric injury, we examined whether renal sodium affects NKCC1 expression and the dynamic pumping function of renal lymphatic vessels. Puromycin aminonucleoside (PAN)-injected rats served as a model of proteinuric kidney injury. Sodium 23Na/1H-MRI was used to measure renal sodium and water content in live animals. Renal lymph, which reflects the interstitial composition, was collected, and the sodium analyzed. The contractile dynamics of isolated renal lymphatic vessels were studied in a perfusion chamber. Cultured lymphatic endothelial cells (LECs) were used to assess direct sodium effects on NKCC1. MRI showed elevation in renal sodium and water in PAN. In addition, renal lymph contained higher sodium, although the plasma sodium showed no difference between PAN and controls. High sodium decreased contractility of renal collecting lymphatic vessels. In LECs, high sodium reduced phosphorylated NKCC1 and SPAK, an upstream activating kinase of NKCC1, and eNOS, a downstream effector of lymphatic contractility. The NKCC1 inhibitor furosemide showed a weaker effect on ejection fraction in isolated renal lymphatics of PAN vs controls. High sodium within the renal interstitium following proteinuric injury is associated with impaired renal lymphatic pumping that may, in part, involve the SPAK-NKCC1-eNOS pathway, which may contribute to sodium retention and reduce lymphatic responsiveness to furosemide. We propose that this lymphatic vessel dysfunction is a novel mechanism of impaired interstitial clearance and edema in proteinuric kidney disease.
Highlights
Sodium retention is a well-documented consequence of many pathophysiological conditions, especially kidney disease, which is clinically recognized as an accumulation of edema [1]
MRI analysis revealed that puromycin aminonucleoside nephropathy (PAN) injury leads to increased renal sodium content
Sodium concentration in concurrently obtained serum samples was not different between PAN rats and controls (Figure 2B). These results indicate that, in addition to the well-documented proteinuria, hypoalbuminemia, and hyperlipidemia, PAN kidney injury leads to intrarenal sodium and water retention, especially in the renal cortex
Summary
Sodium retention is a well-documented consequence of many pathophysiological conditions, especially kidney disease, which is clinically recognized as an accumulation of edema [1]. While kidneys have a central role in regulating sodium homeostasis, few studies have quantified kidney sodium or water content, including in edema-forming conditions. Such studies have been primarily limited by a lack of methodology for sodium quantification in vivo. Lymphatics are important because unlike blood flow, which relies on the heart as a central pump, lymph flow is propelled by forces in the surrounding tissues and by active rhythmic contractions intrinsic to the lymphatic vessels themselves. Whether intrarenal sodium modulates the renal lymphatic contractions has not been reported
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