A new anti-inflammatory compound, FR167653, ameliorates crescentic glomerulonephritis in Wistar-Kyoto rats.
The pathophysiologic effects of FR167653 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar-Kyoto rats. The rats developed crescentic glomerulonephritis by 6 d after the administration of serum. The subcutaneous administration of FR167653 (32 mg/kg) markedly decreased the severity of the renal damage. In a group of rats treated with FR167653 daily from day 0 to day 6, glomerular damage, including crescent formation and proteinuria, was virtually absent. FR167653 markedly decreased urinary levels of monocyte chemoattractant protein-1 (MCP-1). In addition, FR167653 reduced production of MCP-1 protein and transcripts in the diseased kidneys. In a group of rats for which treatment was initiated on day 3, shortly after the appearance of glomerular abnormalities, the progression of renal disease was appreciably retarded, with partial inhibition of MCP-1. In contrast, when rats were treated only on the first day, no beneficial effects were observed and severe proliferative and necrotizing glomerulonephritis, with crescent formation, was induced by day 6, with the upregulation of MCP-1. These results suggest that FR167653 may be effective against crescentic glomerulonephritis, possibly via the inhibition of MCP-1. In addition, there was marked reduction in renal injury even when FR167653 treatment was initiated after glomerular inflammation was established, suggesting that the therapeutic application of FR167653 may be clinically useful for human renal diseases.
Wada
Takashi
T
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Furuichi
Kengo
K
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Sakai
Norihiko
N
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Iwata
Yasunori
Y
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Yoshimoto
Keiichi
K
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Shimizu
Miho
M
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Kobayashi
Ken-Ichi
KI
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
Mukaida
Naofumi
N
Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Matsushima
Kouji
K
Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, Tokyo, Japan.
Yokoyama
Hitoshi
H
First Department of Internal Medicine and Division of Blood Purification, School of Medicine, Kanazawa University, Kanazawa, Japan.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000652:urine; D005921:Glomerulonephritis / Q000473:pathology* / Q000503:physiopathology* / Q000652:urine; D008297:Male; D011507:Proteinuria / Q000652:urine; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; C104334:FR 167653; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger