Kidney Injury Causes Accumulation of Renal Sodium That Modulates Renal Lymphatic Dynamics

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.

Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

“…The IsoLG modified apoAI affected the vascular dynamics of renal-collecting vessel lymphatics, increasing frequency, but reducing EDD, ESD, and amplitude of contraction compared with unmodified apoAI ( Figure 9 ). These results comport with our recent study showing that PAN kidney injury diminishes lymphatic vessel pumping efficiency including reduced amplitude of contraction, which predicts reduced clearance of the renal interstitium ( 36 ). Indeed, 23 Na-MRI revealed significant accumulation of sodium and water in the injured kidneys compared with normal CTLs.…”

Intestinal Lymphatic Dysfunction in Kidney Disease

“…Recently, the lymphatic system has also been recognized as a facilitator of interorgan cross talk under physiological and pathological conditions. 3,5,6 Divided into 3 classes, lymphoid organs are central components of the body’s immune response. Primary lymphoid organs (bone marrow and thymus) contain lymphoid progenitor cells required for lymphocyte differentiation.…”

“…159,171,173 It is, therefore, notable that aside from lymphatic growth, sodium can also modulate lymphatic dynamics, which may have a role in hypertension and other diseases. 5,174,175 Mizuno et al 175 showed high-sodium diet suppressed the amplitude, ejection fraction, and stroke volume that markedly reduced pumping activity in afferent lymphatics while efferent lymphatics were resistant to the effects high-salt diet and preserved pumping reflected increased contraction frequency. High-salt diet or DOCA treatment increased skin and muscle lymphatic vessel contraction frequency while reducing contraction amplitude.…”

“…174 Similarly, we showed that direct exposure of lymphatic vessels to a high-sodium environment increases the frequency of contraction of collecting lymphatic vessels and reduced the contraction amplitude and, to a lesser extent, the ejection fraction. 5 Currently, there are no studies specifically assessing the effects of sodium on mesenteric lymphatics; however, it is known that this lymphatic bed adapts to physiologic and pathophysiologic stimuli. For example, oxidative stress, fructose feeding, aging, and intestinal inflammation impair intrinsic contractility of the mesenteric collecting lymphatic vessels.…”

Lymphangiogenesis and Lymphatic Barrier Dysfunction in Renal Fibrosis

“…Kidney plays a major role in modulating sodium reabsorption as well as excretion, and various renal diseases are accompanied by sodium retention. We previously proved intrarenal sodium accumulation and elevated sodium concentration in renal lymph, causing the dysfunction of renal collecting LVs through Na-K-2Cl cotransporter NKCC1 [106]. Would accumulating interstitial sodium influence permeability of LVs or promote lymphangiogenesis through tonicity-related signaling such as cardiovascular disease?…”