Single-Cell RNA Sequencing Reveals Roles of Renal Lymphatic Endothelial Cells in Cisplatin Induced Acute Kidney Injury

Abstract

In the United States an estimated 50% of ICU patients develop Acute Kidney Injury (AKI) which is associated with a 50% mortality rate. A single occurrence of AKI predisposes a patient to develop chronic conditions such as Chronic Kidney Disease (CKD). The mechanism of the AKI to CKD transition is still unknown but is likely mediated by the extent and length of the inflammatory response following the initial injury. Lymphatic vessels help to maintain tissue homeostasis through fluid, macromolecule, and immune modulation. Increased lymphatic growth, or lymphangiogenesis, often occurs during inflammation and plays a role in acute and chronic disease processes. We have previously demonstrated that an expanded lymphatic network in KidVD mice increases the CD4:CD8 Tcell ratio and that this may afford protection from an AKI-to-CKD transition. The primary objective of this study was to understand what roles renal lymphatic endothelial cells (LECs) play in AKI recovery and CKD progression, a role which remains largely unknown. To determine if LECs have protective immunomodulatory roles in kidney injury, we utilized male C57/BL6 mice and a single 20 mg/kg Cisplatin dose to induce AKI and isolated renal LECs 72hrs post-injury. Using Seurat, ENRICHR, and STRING protein interaction analyses we defined and identified three LEC populations. Upon Cisplatin injury differences in gene expression revealed alterations in signaling pathway enrichment for (1) immunoregulatory interactions; (2) blood and lymphatic vessel development; and (3) T cell development. These findings illustrate specific differences in immune pathway activation between uninjured and injured renal LECs in regulating the inflammatory response in AKI. Together, this data indicates renal LECs may alter immunological outcomes in injury and uncovers previously unknown molecular roles in kidney injury. NIDDK R01(JMR): 1R01DK119497-01A1, AHA Predoctoral Fellowship (HAC): 916334 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.