Single-cell RNA sequencing identifies response of renal lymphatic endothelial cells to acute kidney injury

Abstract

The inflammatory response to acute kidney injury (AKI) likely dictates future renal health. Lymphatic vessels are responsible for maintaining tissue homeostasis through transport and immunomodulatory roles. Due to the relative sparsity of lymphatic endothelial cells (LECs) in the kidney, past sequencing efforts have not characterized these cells and their response to AKI. Here we characterized murine renal LEC subpopulations by single-cell RNA sequencing and investigated their changes in cisplatin AKI. We validated our findings by qPCR in LECs isolated from both cisplatin-injured and ischemia reperfusion injury, by immunofluorescence, and confirmation in in vitro human LECs. We have identified renal LECs and their lymphatic vascular roles that have yet to be characterized in previous studies. We report unique gene changes mapped across control and cisplatin injured conditions. Following AKI, renal LECs alter genes involved endothelial cell apoptosis and vasculogenic processes as well as immunoregulatory signaling and metabolism. Differences between injury models are also identified with renal LECs further demonstrating changed gene expression between cisplatin and ischemia reperfusion injury models, indicating the renal LEC response is both specific to where they lie in the lymphatic vasculature and the renal injury type. How LECs respond to AKI may therefore be key in regulating future kidney disease progression.

Kidney Endothelial Cell Biology in Health and Disease

“…In this issue of JASN , Creed et al provide additional insights into the implications of lymphatic biology for kidney diseases. 3 By exploring the altered gene expression changes in response to cisplatin-induced AKI in male mice, the investigators identified the lymphatic endothelial cells (LECs) molecular signature as being most consistent with vascular endothelial growth factor receptor signaling, T-cell differentiation, and regulation of inflammatory response, supporting the notion that LECs respond to AKI by undergoing lymphangiogenesis and upregulating their interactions with immune cells. In addition, by comparing the molecular responses of LECs to distinct injury stimuli (cisplatin versus ischemia–reperfusion injury), the investigators revealed that the response of LECs is likely influenced by the specific mode and context of injury, thereby substantiating the existing evidence of conflicting outcomes in the literature across different models.…”