Inflammation-mediated Upregulation of VCAM-1 but not KIM-1 during Acute Kidney Injury to Chronic Kidney Disease Transition

Abstract

Background: Patients with acute kidney injury (AKI) have higher risks of developing chronic kidney disease (CKD). The basis for the AKI-to-CKD transition remains poorly understood, but studies in animal models suggest a linkage between the inflammatory response to injury and subsequent nephron loss and interstitial fibrosis. The proximal tubule is the primary venue of injury and progression of disease during this process. Methods: Mouse unilateral ischemia/reperfusion injury (U-IRI) model was used to study the kinetics of proximal injury marker expression during AKI-to-CKD transition. Immortalized MPT cells and primary cultured renal cells were used to study factor(s) that induce vascular cell adhesion protein-1 (VCAM-1) expression in proximal tubule cells. Results: Kidney injury molecule-1 (KIM-1) was rapidly upregulated on day 1 after injury and gradually reduced close to the baseline; whereas VCAM-1 was not upregulated on day 1 but markedly increased afterwards during AKI-to-CKD transition. The proximal tubular VCAM-1 expression is induced by proinflammatory cytokines including TNFα and IL-1β. Blockade of these signaling pathways by using NF-κB inhibitor or by using double null mutant Myd88 and Trif derived PCRC in vitro or decrease of immune cell recruitment using Ccr2 null mouse in vivo significantly suppressed VCAM-1 expression. Human single cell transcriptome analysis identified a distinct cluster of injured proximal tubules that highly expressed VCAM1 but not HAVCR1 (KIM1), and the population of these VCAM1-positive proximal tubule cells was associated with CKD progression and VCAM-1 levels were significantly higher in the patients with Stage 3 CKD as compared to the healthy references. Conclusions: Proximal tubule cells upregulated KIM-1 and VCAM-1 in an orchestrated fashion after injury. Upregulation of VCAM-1 associated with chronic tubular injury and interstitial fibrosis and may mark the earliest molecular event during AKI-to-CKD transition.

Predicting regulators of epithelial cell state through regularized regression analysis of single cell multiomic sequencing

“…Profibrotic, proinflammatory PT cell states have been increasingly predicted to play a role in CKD development following incomplete PT repair following acute injury or during chronic progressive disease (10,14,28,56). Here we performed joint single nucleus RNA and ATAC sequencing on adult human kidney samples to study the PT_VCAM1 state in adult human kidney.…”