#2199 Fibroblast-macrophage dynamics and midkine signaling in ischemic induced renal fibrosis

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Abstract Background and Aims Understanding the process of fibrotic deposition by resident renal fibroblasts provides crucial insights into the mechanisms underlying renal fibrosis. Utilizing a unilateral ischemia-reperfusion injury (uIRI) mouse model, we aimed to identify the specific cell populations involved in fibrosis, assess how these cells are influenced by various signaling factors secreted through intercellular interactions, and characterize changes in gene expression associated with this process. Method To establish an acute kidney injury (AKI) to chronic kidney disease (CKD) transition model, the left kidney of mice was subjected to 30 minutes of ischemia followed by reperfusion. Kidneys were harvested on days 10 and 20 post-surgery. Single-cell RNA sequencing (scRNA-seq) was performed on whole kidney samples at each time point. Cell clustering and differential gene expression (DEG) analyses were conducted, along with analyses of incoming and outgoing interaction strengths to elucidate cell-to-cell communication dynamics. Results Fibroblasts and macrophages exhibited the highest incoming and outgoing interaction strengths at both days 10 and 20, highlighting their central roles in the reperfusion injury environment. These cell populations were identified as key upstream regulators in the pathophysiological progression of fibrosis. A more detailed analysis of macrophage subtypes revealed a significant increase in the proportion of IL-10-positive macrophages on day 20. Additionally, in the group analyzed 20 days post-uIRI, increased gene expression related to the midkine signaling pathway was observed, coinciding with enhanced fibroblast-macrophage interaction strength. Conclusion In summary, IL-10, macrophages, and fibroblasts play pivotal roles in the transition from AKI to CKD in the ischemia-reperfusion injury model. These processes appear to be regulated, at least in part, by midkine signaling, providing new insights into the molecular and cellular mechanisms of renal fibrosis.

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