CD44-Positive Cells and Hyaluronan are a Hallmark of a Rat Model of Aristolochic Acid Nephropathy

Anne-Emilie Decleves Agnieszka Pozdzik

doi:10.4172/2157-7099.1000186

Anne-Emilie Decleves Agnieszka Pozdzik

Open Access

https://doi.org/10.4172/2157-7099.1000186

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Abstract

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.

Highlights

Called Chinese herb nephropathy, Aristolochic Acid Nephropathy (AAN) was reported in 1992 in young Belgian women after intake of slimming pills containing root extracts of Aristolochia sp. [1,2]
Prominent collagen deposits and TGF-ß expression, impaired tubular regeneration [7], as well as massive inflammatory cells infiltration [3] are hallmarks of experimental AAN. The latter has a biphasic evolution with an acute early phase (3-10 days) of tubular necrosis followed by a chronic phase of interstitial fibrosis and tubular atrophy [3,5]
NAG enzymuria significantly increased from day 3 to day 35 (Figure 1C), reflecting structural impairment of Proximal Tubular Epithelial Cell (PTEC) [5]

Summary

Introduction

Called Chinese herb nephropathy, Aristolochic Acid Nephropathy (AAN) was reported in 1992 in young Belgian women after intake of slimming pills containing root extracts of Aristolochia sp. [1,2]. AAN is a progressive chronic Tubulointerstitial (TI) disease characterized by tubular atrophy and dense TI fibrosis with relatively well-preserved glomeruli [1,3]. Prominent collagen deposits and TGF-ß expression, impaired tubular regeneration [7], as well as massive inflammatory cells infiltration [3] are hallmarks of experimental AAN. The latter has a biphasic evolution with an acute early phase (3-10 days) of tubular necrosis followed by a chronic phase (after 14 days) of interstitial fibrosis and tubular atrophy [3,5]. We examined the distribution of CD44, an adhesion molecule involved in differentiation, and its main ligand, Hyaluronan (HA), in an experimental AAN model

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