title: ONO-1301, a sustained-release prostacyclin analog, ameliorates the renal alterations in a mouse type 2 diabetes model possibly through its protective effects on mesangial cells.
abstract: Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-β1, α-smooth muscle actin (α-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-β, type IV collagen, α-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells.
authors.affiliation: Departments of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watatani
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeshima
authors.forename: Tatsuyo
authors.initials: T
authors.lastname: Nasu
authors.forename: Norikazu
authors.initials: N
authors.lastname: Hinamoto
authors.forename: Haruyo
authors.initials: H
authors.lastname: Ujike
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology; D024141:Collagen Type IV / Q000032:analysis; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D008055:Lipids / Q000097:blood; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress; D011725:Pyridines / Q000097:blood / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000199:Actins; D001786:Blood Glucose; D018932:Chemokine CCL2; D024141:Collagen Type IV; D003692:Delayed-Action Preparations; D008055:Lipids; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C491768:Ccl2 protein, mouse; C498862:Acta2 protein, rat; C105488:ONO 1301