Mizoribine Ameliorates the Tubulointerstitial Fibrosis of Obstructive Nephropathy

Abstract

Mizoribine has been shown to possess an immunosuppressive action that inhibits the proliferation of lymphocytes selectively by interfering with inosine monophosphate dehydrogenase. Recent studies have demonstrated that mizoribine improves renal tubulointerstitial fibrosis in the rat model of unilateral ureteral obstruction (UUO) by inhibiting the infiltration of macrophages. We, therefore, examined the dose dependency of the suppressive effect of mizoribine on the infiltration of interstitial macrophages and T lymphocytes and the interstitial volume in UUO-treated kidneys. Furthermore, we investigated the expression of osteopontin (OPN), known to be a chemoattractant protein for macrophages, in the renal cortex. In rats with UUO, the interstitial volume was markedly expanded, and macrophage and T lymphocyte infiltration in the interstitium and the expression of OPN in the cortical tubules were greatly increased. Treatment with mizoribine ameliorated the increase in interstitial volume induced by UUO. Interstitial infiltration of macrophages and T lymphocytes was dose dependently suppressed by mizoribine, and the decreased macrophage infiltration was correlated with inhibition of tubular OPN expression. These results suggest that mizoribine has a beneficial effect on several steps contributing to the progression of tubulointerstitial fibrosis caused by obstruction of the ureter.

Protective Effects of Mizoribine on Cyclosporine A Nephropathy in Rats

“…MZR treatment decreases macrophage infiltration, OPN, and TGF-beta expression and this is associated with improved histopathology, in an animal model of unilateral ureteral obstruction (5). Although, in our study, MZR treatment did not significantly suppress OPN mRNA expression in the rats receiving CsA, a tendency to decrease the OPN level seemed to be accepted.…”

“…Recent studies have demonstrated that MZR suppresses the infiltration of macrophages, which play an important role in the development of interstitial fibrosis and ameliorate the interstitial fibrosis of obstructive nephropathy in rats (4,5). However, its effect has not yet been reported in the CsAtreated rat kidney.…”

Mizoribine Suppresses Proliferation of Rat Glomerular Epithelial Cells in Culture and Inhibits Increase of Monocyte Chemoattractant Protein-1 and Macrophage Inflammatory Protein-2 Stimulated by Thrombin

“…[27][28][29] Recently, Tanaka et al reported MZR attenuates renal injury and intraglomerular infiltration of macrophages in patients with severe lupus nephritis. 30) It is suggested that MZR inhibits MCP-1 production by GEC and may block the infiltration of intraglomerular macrophages.…”

Treatment of Pediatric-Onset Lupus Nephritis: A New Option of Less Cytotoxic Immunosuppressive Therapy

“…Besides its immunosuppressive effects, MZR has recently been reported to suppress the progression of histologic chronicity in selected patients with lupus nephritis and IgA nephropathy (Kawasaki et al, 2004;Tanaka et al, 2007b and c;Ikezumi et al, 2008). Moreover, MZR has been reported to attenuate tubulointerstitial fibrosis in a dosedependent manner in rat models of unilateral ureteral obstruction, non-insulin-dependent diabetes and peritoneal fibrosis via suppression of macrophage infiltration of the interstitium (Sato et al, 2001;Kikuchi et al, 2005;Takahashi et al, 2009). Interestingly, MZR has been reported to bind specifically to heat shock protein (HSP) 60, which results in interference of the chaperone activity of HSP60 in vitro (Itoh et al, 1999).…”