Increased synthesis of CD44s and its variants in kidney fibrosis of lupus nephritis

Abstract

BACKGROUND: Lupus nephritis is characterized by immune-mediated renal injury leading to glomerular and tubulo-interstitial fibrosis. CD44 is the major cell surface receptor for hyaluronan (HA) which has been implicated in inflammatory and fibrotic processes. During pathological conditions, splice variants of CD44 may also be induced. We investigated renal expression of standard CD44 (CD44s) and its variants in patients and mice with lupus nephritis, and their role in renal fibrosis. METHODS: CD44s, CD44v3 and CD44v6 expression was determined in kidney biopsies from patients with diffuse proliferative lupus nephritis and normal kidney tissue using cytochemical staining. Expression of CD44s, CD44v3 and CD44v6 was examined in NZB/W mice during disease progression. Mesangial cells were isolated from the renal cortex of NZB/W mice to investigate the mechanisms of CD44 synthesis. RESULTS: There was intense staining for CD44s and its variants in the glomeruli and renal tubules in kidney biopsies from patients with lupus nephritis, compared with weak expression in controls. CD44v3, but not CD44s and CD44v6, was also noted in cells infiltrating the glomerulus, peri-glomerular area, and interstitium. Compared to mice before the development of nephritis, murine renal cortical CD44s gene expression was significantly higher during active nephritis (proteinuria >3g/l), and continued to increase during progressive glomerular and tubulo-interstitial fibrosis (P<0.01 and P<0.001 respectively). CD44s, CD44v3 and CD44v6 expression in NZB/W mice was associated with glomerular and tubulo-interstitial fibrosis. Glomerular CD44s co-localized with collagen deposition, while tubulo-interstitial CD44s expression was associated with inflammatory cell infiltration, tubular atrophy and tubulo-interstitial fibrosis. CD44s, CD44v3 and CD44v6 were constitutive expressed in mesangial cells from NZB/W mice. Stimulation of mesangial cells with HA, IL-6, IL-1b, TNF-a, but not IFN-g, increased CD44s and CD44v3 but not CD44v6 synthesis. CONCLUSIONS: Our data suggested a role of CD44s and its variants in renal fibrosis due to lupus nephritis, and the modulatory effect of pro-inflammatory cytokines on their expression.