**1. Introduction**

Sodium retention is a well-documented consequence of many pathophysiological conditions, especially kidney disease, which is clinically recognized as an accumulation of edema [1]. Previous studies found sodium retention in skin and muscle is connected to blood pressure regulation involving lymphatic remodeling [2–4]. Recent research indicates that sodium, along with water, accumulates systemically, including in the lung, liver,

**Citation:** Liu, J.; Shelton, E.L.; Crescenzi, R.; Colvin, D.C.; Kirabo, A.; Zhong, J.; Delpire, E.J.; Yang, H.-C.; Kon, V. Kidney Injury Causes Accumulation of Renal Sodium That Modulates Renal Lymphatic Dynamics. *Int. J. Mol. Sci.* **2022**, *23*, 1428. https://doi.org/10.3390/ ijms23031428

Academic Editors: Márcia Carvalho and Luís Belo

Received: 21 December 2021 Accepted: 20 January 2022 Published: 27 January 2022

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muscle, and myocardium [5,6]. 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. Recent developments in noninvasive sodium imaging by 23Na-MRI provide an attractive tool for quantifying kidney sodium content in vivo. Moreover, although kidney disease is regularly accompanied by lymphatic vessel hyperplasia [7–14], whether disease-induced lymphangiogenesis is accompanied by disrupted renal lymphatic vessel dynamics is unknown. 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. These intrinsic mechanisms constitute a major force in lymphatic flow and are exquisitely sensitive to the microenvironment, for example, hydraulic pressure, shear stress, local tissue temperature, and sodium [15]. A recent study provides evidence that lymphangiogenesis accompanying arthritis in TNF-transgenic mice reflects intrinsic dysfunction in popliteal lymphatic vessels that is linked to NOSdependent as well as independent impairment in lymphatic vessel dynamics that may drive arthritic damage of the joint [16]. Whether intrarenal sodium modulates the renal lymphatic contractions has not been reported.

Lymphatic vessel contractility is driven by action potentials that trigger Ca++ influx generated by ion channels and transporters. We recently showed the Na-K-2Cl cotransporter NKCC1, but not NKCC2, is expressed in renal lymphatic vessels [17]. While NKCC2 is best known for its actions on tubular epithelial cells responsible for the maintenance of sodium homeostasis, NKCC1 is increasingly recognized as a modulator of various unanticipated biological functions, including regulation of vascular tone [18]. Indeed, inhibition of NKCC1 and its activating kinases has become a novel antihypertensive strategy involving direct (non-diuretic) vascular dilation. However, in contrast to blood vessels, little is known about NKCC transporter expression, activity, or function in the lymphatic vascular network and how the microenvironment or disease alters these parameters. This is particularly relevant since the first line of intervention in the treatment of edema and underlying interstitial clearance impairment is NKCC inhibition by furosemide.

Here we assessed whether kidney injury affects renal sodium content, how a highsodium environment alters the pumping dynamics of renal collecting lymphatic vessels, and the role of NKCC1 in this response.
