Mizoribine ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.
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.
Sato
N
N
Laboratory for Toxicological Research, Institute for Life Science Research, Asahi Chemical Industry Co., Ltd., Shizuoka, Japan. sato.nc@om.asahi-kasei.co.jp
Shiraiwa
K
K
Kai
K
K
Watanabe
A
A
Ogawa
S
S
Kobayashi
Y
Y
Yamagishi-Imai
H
H
Utsunomiya
Y
Y
Mitarai
T
T
D000818:Animals; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D053495:Osteopontin; D051381:Rats; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000494:pharmacology*; D012795:Sialoglycoproteins / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; C010052:mizoribine