Serum and renal expression of CD44s and its variants correlate with disease activity in lupus nephritis

Abstract

INTRODUCTION: Lupus nephritis is characterized by immune-mediated kidney injury. CD44 is a major cell surface receptor for hyaluronan, which has been implicated in inflammatory and fibrotic processes. Also, splice variants of CD44 can be induced under disease states. We investigated serum levels and renal expression of standard CD44 (CD44s) and its variants in human and murine lupus nephritis, focusing on its role in renal fibrosis. METHODS: Circulating level of CD44s was measured in paired sera from 56 patients with biopsy-proven diffuse proliferative lupus nephritis, during active disease and remission respectively, using ELISA. Healthy subjects (n=36) and patients with non-lupus glomerular diseases (n=37) were included for comparison. CD44s, CD44v3 and CD44v6 expression was determined in kidney biopsies from patients and in NZBWF1/J mice with cytochemical staining. Mesangial cells were isolated from NZBWF1/J mice to investigate the mechanisms of CD44 synthesis. RESULTS: Patients with active lupus nephritis showed significantly higher serum CD44s level than lupus nephritis patients in remission, glomerular disease controls, and healthy subjects (P<0.001 for all). Serum CD44s level in lupus nephritis patients correlated with the level of anti-dsDNA antibody (r=0.43, P<0.001) and serum creatinine (r=0.46, P<0.0001), and inversely correlated with C3 (r=-0.45, P<0.001). Kidney biopsies from patients with active lupus nephritis showed intense staining for CD44s and its variants in the glomeruli and renal tubules compared with weak expression in healthy kidney tissue. CD44v3, but not CD44s and CD44v6, was observed in inflammatory cells that infiltrate the glomerulus and interstitium. Renal cortical CD44s mRNA expression increased with progression of nephritis in NZBWF1/J mice, and the increase in CD44s, CD44v3 and CD44v6 expression was associated with inflammatory cell infiltration, glomerular and tubulo-interstitial fibrosis, and tubular atrophy. CD44s, CD44v3 and CD44v6 were constitutive expressed in mesangial cells from NZBWF1/J mice. Hyaluronan, IL-6, IL-1beta, TNF-alpha, but not IFN-gamma, increased CD44s and CD44v3 (but not CD44v6) synthesis in murine mesangial cells. CONCLUSIONS: Our data suggest that CD44s and its variants are involved in the pathogenesis of renal inflammation and fibrosis in lupus nephritis.