**5. Conclusions**

Based on our data, we propose that dysfunction of renal lymphatic vessels is related to electrolyte abnormalities. Furthermore, although lymphangiogenesis has been firmly established to accompany these conditions, our data suggest that sodium-induced lymphatic dysfunction compounds the problem of impaired fluid clearance in the setting of kidney injury. Sodium accumulation suppresses the pumping function of renal lymphatic vessels by inhibiting the SPAK-NKCC1 cascade. These results imply that the lymphatic system should be viewed as a potential target in disease characterized by sodium accumulation, such as various renal diseases or heart failure.

**Author Contributions:** Conceptualization, V.K.; Methodology, J.L., E.L.S., R.C., D.C.C., J.Z. and H.-C.Y.; Software, J.L, E.L.S., R.C., D.C.C., J.Z. and H.-C.Y.; Validation, J.L., E.L.S., R.C., D.C.C. and H.-C.Y.; Formal Analysis, J.L., E.L.S., R.C., D.C.C. and H.-C.Y.; Resources, J.L., E.L.S., R.C., D.C.C., A.K., E.J.D. and H.-C.Y.; Writing—Original Draft Preparation, J.L., E.L.S. and R.C., Writing—Review & Editing, J.L., E.L.S., R.C., D.C.C., A.K., E.J.D., H.-C.Y. and V.K.; Visualization, J.L., E.L.S., D.C.C., A.K., H.-C.Y. and V.K.; Project Administration, H.-C.Y. and V.K.; Funding Acquisition, V.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** The work was supported by NIH 1P01HL116263, K01HL13049, R03HL155041 and R01HL144941.

**Institutional Review Board Statement:** All procedures were approved by the Institutional Animal Care and Use Committee of VUMC and conducted according to the NIH's *Guide for the Care and Use of Laboratory Animals* (National Academies Press, 2011).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data and other materials can be obtained from authors.

**Conflicts of Interest:** The authors declare no conflict of interest.
