CD44 expression in renal tubules during maladaptive repair is a potential marker for the transition from acute kidney injury to chronic kidney disease in rats.

Abstract

Renal tubular epithelial cells (TECs) are major targets of drug-induced kidney injury, a cause of acute kidney injury (AKI). Although TEC regeneration aids recovery, maladaptive repair promotes fibrosis and chronic kidney disease (CKD). CD44 has been reported to localize predominantly to dilated/atrophic TECs in the fibrotic lesions of rat CKD models, suggesting enrichment in failed-repair TECs, but its dynamics during the AKI-to-CKD transition are unclear. We examined CD44 across rat models spanning adaptive repair and AKI-to-CKD transition induced by renal ischemia/reperfusion (I/R; 30 or 60 min) or cisplatin nephrotoxicity (2 or 6 mg/kg, i.p.) through day 28. In the AKI-to-CKD transition settings (I/R 60 min and cisplatin 6 mg/kg), CD44 was induced in dilated/atrophic TECs before fibrosis. Re-analysis of mouse I/R single-cell RNA-seq confirmed Cd44 enrichment in maladaptive TEC clusters. In the cisplatin model, serum CD44 rose early and remained elevated after conventional markers normalized, paralleling renal CD44 induction. Microarray profiling of microdissected dilated/atrophic TECs revealed a matrix-associated signature. Immunohistochemistry showed reduced aquaporin 1, vimentin induction, and that CD44tubules remained enclosed by a laminin-positive basement membrane. Pathway analysis predicted CD44 as a putative upstream regulator of fibrosis-related genes including Fn1; increased Fn1 mRNA in dilated/atrophic TECs with peritubular fibronectin accumulation suggested a possible tubular contribution to matrix deposition. Together, these findings support tissue CD44 as a candidate marker of maladaptive tubular repair during the AKI-to-CKD transition and suggest serum CD44 as a candidate circulating indicator in cisplatin nephrotoxicity.