VCAM-1 mediates proximal tubule-immune cell cross talk in failed tubule recovery during AKI-to-CKD transition
Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-a and interleukin (IL)-1ß. Analyses of bulk RNA sequencing of TNF-a-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-?B and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-?B signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-ß suppressed TNF-a- and IL-1ß-induced VCAM-1 expression in vitro. TNF-a stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-?B-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD. Overall design: To study the mechanism(s) of VCAM-1 induction and its role in promoting immune cell adhesion, we used primary cultured renal cells (PCRCs) that were treated with TNFa ± NF-?B-specific inhibitor, ACHP. We then performed gene expression profiling analysis using data obtained from RNA-seq of PCRCs treated with PBS, TNFa, and TNFa+ACHP.