CD44-positive cells and hyaluronan are a hallmark of a rat model of aristolochic acid nephropathy

Background: Aristolochic acid (AA) Nephropathy (AAN) is characterized by tubulointerstitial injury leading to fibrosis and tubular atrophy. Defective regeneration of tubular cells was hypothesized as a mechanism leading to Proximal Tubular Epithelial Cell (PTEC) atrophy. Here, we examined the distribution of CD44, an adhesion molecule involved in differentiation, and its main ligand, Hyaluronan (HA), in an experimental AAN model. Methods: Wistar rats were injected daily with AA or vehicle during 35 days. Tubular enzymuria and tissue expression of CD44 and HA were evaluated at days 3, 7, 10, 21 and 35. Co-expressions of CD44 and PCNA (proliferation), vimentin (mesenchymal phenotype), a-SMA (myofibroblasts), and CD133 (progenitor cells) were investigated. Results: AA induced acute tubular damage followed by PTEC atrophy. In controls, CD44 was limited to the basolateral membrane of collecting ducts while HA expression was confined to the medullary interstitium. CD44 was overexpressed as soon as 3 days after AA exposure, spreading to the apical and basolateral membranes of dedifferentiated PTECs and appearing on numerous interstitial cells along with marked HA accumulation around necrotic tubules. Both CD44 and HA expressions increased steadily throughout the 1-month follow-up. A large amount of tubular and interstitial CD44+ cells were proliferative (PCNA+) and mesenchymal-like (vimentin+). Few CD44+ cells expressed a-SMA or CD133. Conclusions: Our results suggest CD44 is a strong marker of dedifferentiation, and thus of regeneration, in a rat model of AAN. Concomitant HA accumulation around necrotic tubules may create a sustained crosstalk between CD44+ cells and their interstitial ligand. PTEC atrophy is accompanied by overexpression, not deficiency, of the CD44-HA axis.