Clusterin marks maladaptive regenerative responses throughout the kidney following ischemia-reperfusion injury

Our understanding of the regenerative capacity of renal tubules has primarily come from studies focusing on proximal tubules. To gain a broader view of injury responses throughout the tubular network, we employed single-cell RNA sequencing (scRNA-seq) and lineage tracing to dissect cells expressing Clusterin (Clu), a known biomarker of kidney disease. During development, Clu labeled nephrogenic progenitors, while in response to ischemia-reperfusion injury, Clu was initially upregulated in distal segments. Fate mapping demonstrated that Clu+ collecting ducts were proliferative but ultimately persisted in a de-differentiated state or were lost. By scRNA-seq following IRI, we identified delayed and maladaptive responses in injured proximal tubules and uncovered a "mixed lineage" gene signature comprised of podocyte and parietal epithelial cell markers aberrantly activated in diverse cell types within the medulla. In conclusion, despite labeling multipotent progenitors during nephrogenesis, Clu reactivation in the injured adult kidney signals impaired regenerative responses throughout the tubular epithelium.