Emerging roles for lymphatics in acute kidney injury: Beneficial or maleficent?

Abstract

Acute kidney injury, a sudden decline in renal filtration, is a surprisingly common pathology resulting from ischemic events, local or systemic infection, or drug-induced toxicity in the kidney. Unchecked, acute kidney injury can progress to renal failure and even recovered acute kidney injury patients are at an increased risk for developing future chronic kidney disease. The initial extent of inflammation, the specific immune response, and how well inflammation resolves are likely determinants in acute kidney injury-to-chronic kidney disease progression. Lymphatic vessels and their roles in fluid, solute, antigen, and immune cell transport make them likely to have a role in the acute kidney injury response. Lymphatics have proven to be an attractive target in regulating inflammation and immunomodulation in other pathologies: might these strategies be employed in acute kidney injury? Acute kidney injury studies have identified elevated levels of lymphangiogenic ligands following acute kidney injury, with an expansion of the lymphatics in several models post-injury. Manipulating the lymphatics in acute kidney injury, by augmenting or inhibiting their growth or through targeting lymphatic-immune interactions, has met with a range of positive, negative, and sometimes inconclusive results. This minireview briefly summarizes the findings of lymphatic changes and lymphatic roles in the inflammatory response in the kidney following acute kidney injury to discuss whether renal lymphatics are a beneficial, maleficent, or a passive contributor to acute kidney injury recovery.

Expanded renal lymphatics improve recovery following kidney injury

“…Lymphangiogenesis has been demonstrated in multiple models of renal injury (Creed & Rutkowski, 2021 ; Zarjou et al, 2019 ). To determine whether proteinuric injury following podocyte loss induced renal lymphangiogenesis, LYVE‐1, and podoplanin immunolabeling were performed and quantified.…”

“…Similar to these findings, our study identified a significant increase in lymphatic density in response to a progressive proteinuric kidney injury or IRI by day 7 post‐injury. Lymphatic vessels and renal lymphangiogenesis following kidney injury have been reported to be beneficial in some models by reducing fibrosis and increasing functional recovery, while others have reported detrimental injury outcomes due to lymphatic propagation of a pro‐inflammatory innate immune response (Creed & Rutkowski, 2021 ).…”

“…Lymphatic vessels and lymphangiogenesis are reported to play multiple beneficial and detrimental roles following AKI, therefore the precise role of lymphatics in kidney injury remain unclear (Creed & Rutkowski, 2021 ). The current study demonstrates a significant positive impact of increased lymphatic density in the kidney prior to injury that improves functional recovery post‐AKI.…”

“…Lymphatic vessel hyperplasia, expression of lymphatic growth factors, and de novo lymphangiogenesis have been reported in multiple forms of clinical and pre‐clinical AKI (Black et al, 2019 ; Karlsen et al, 2018 ; Zarjou et al, 2019 ). Whether lymphatic vessels and lymphangiogenesis play positive or negative roles following kidney injury is still unclear (Creed & Rutkowski, 2021 ). Historically, lymphatic vessels and lymphatic endothelial cells (LECs) were thought to be a purely passive system; however, recent research has increasingly demonstrated that lymphatics have active immunomodulatory roles that may impact inflammation resolution (Petrova & Koh, 2020 ).…”

Single-Cell RNA Sequencing Identifies Response of Renal Lymphatic Endothelial Cells to Acute Kidney Injury

“…For whole-mount imaging, kidneys from C57BL6/J mice were prepared by cardiac perfusion with warm saline, perfusion fixation with 37°C 1% paraformaldehyde, followed by postfixation overnight at 4°C in 3% paraformaldehyde. For whole-mount immunohistochemistry, tissues were incubated for 20 minutes in increasing percentage methanol washes (20,40,60, and 100) before permeabilization with a 1:4 (volume/volume) DMSO/methanol solution (Dent's). Tissue bleaching was accomplished with 20minute incubations of ice-cold H 2 O 2 (0.1%, 0.3%, and 1% in Dent's solution).…”