title: Sustained-release prostacyclin analog ONO-1301 ameliorates tubulointerstitial alterations in a mouse obstructive nephropathy model.
abstract: Tubulointerstitial injuries are crucial histological alterations that predict the deterioration of renal function in chronic kidney disease. ONO-1301, a novel sustained-release prostacyclin analog, accompanied by thromboxane synthase activity, exerts therapeutic effects on experimental pulmonary hypertension, lung fibrosis, cardiomyopathy, and myocardial ischemia, partly associated with the induction of hepatocyte growth factor (HGF). In the present study, we examined the therapeutic efficacies of ONO-1301 on tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO). After inducing unilateral ureteral obstruction in C57/BL6J mice, a single injection of sustained-release ONO-1301 polymerized with poly (D,L-lactic-co-glycolic acid) sustained-release ONO-1301 (SR-ONO) significantly suppressed interstitial fibrosis, accumulation of types I and III collagen, increase in the number of interstitial fibroblast-specific protein-1 (FSP-1)(+) cells, and interstitial infiltration of monocytes/macrophages (F4/80(+)) in the obstructed kidneys (OBK; day 7). Treatment with SR-ONO significantly suppressed the increase of the renal levels of profibrotic factor TGF-β and phosphorylation of Smad2/3, and elevated the renal levels of HGF in the OBK. In cultured mouse proximal tubular epithelial cells (mProx24), ONO-1301 significantly ameliorated the expression of fibroblast-specific protein-1 and α-smooth muscle actin as well as phosphorylation of Smad3 and increased the expression of zonula occludens-1 and E-cadherin in the presence of TGF-β1 as detected by immunoblot and immunocytochemistry, partly dependent on PGI(2) receptor-mediated signaling. Administration of rabbit anti-HGF antibodies, but not the control IgG, partly reversed the suppressive effects of SR-ONO on tubulointerstitial injuries in the OBK. Taken together, our findings suggest the potential therapeutic efficacies of ONO-1301 in suppressing tubulointerstitial alterations partly mediated via inducing HGF, an antifibrotic factor counteracting TGF-β.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tatsuyo
authors.initials: T
authors.lastname: Nasu
authors.forename: Masaru
authors.initials: M
authors.lastname: Kinomura
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Su Le
authors.initials: SL
authors.lastname: Htay
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saito
authors.forename: Norikazu
authors.initials: N
authors.lastname: Hinamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watatani
authors.forename: Haruyo
authors.initials: H
authors.lastname: Ujike
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeshima
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology*
chemical_list: D011725:Pyridines; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C105488:ONO 1301; D003094:Collagen