Effects of a new synthetic selectin blocker in an acute rat thrombotic glomerulonephritis.
In an attempt to explore a novel therapeutic approach, a new synthetic sulfatide derivative (SKK60037) was evaluated in an acute rat model of P-selectin and leukocyte-dependent thrombotic glomerulonephritis (TG). In vitro, SKK60037 inhibits the function of P- and L-selectin more effectively than sialyl Lewis X (sLe(x)), a well-established selectin blocker. TG was induced by the intravenous administration of nephrotoxic globulin (NTG) to rats pretreated with a subclinical dose of lipopolysaccharide. In this model, platelet accumulation was remarkable within 10 minutes after induction of disease, followed by the infiltration of leukocytes, mainly neutrophils and macrophages. Thrombus formation and fibrinogen deposition in the glomeruli were observed within 1 hour, and they proceeded until 6 hours. P-selectin was highly expressed in glomeruli, whereas E-selectin and L-selectin ligands were not detected. We tested the effects of SKK60037 in this model in comparison with sLe(x) and antirat P-selectin monoclonal antibody (ARP2-4). SKK60037 blocked platelet accumulation in glomerular capillaries at 10 minutes after NTG injection. At 6 hours, leukocyte infiltration and thrombosis were significantly suppressed. Protective effects of SKK60037 were similar to those of ARP2-4, whereas sLe(x) showed minimum effect. The superior effects and more favorable characteristics of SKK60037 to sLe(x) suggest the potential of SKK60037 for clinical application.
Ito
I
I
Third Department of Internal Medicine, Nagoya University School of Medicine, Aichi, Japan.
Yuzawa
Y
Y
Mizuno
M
M
Nishikawa
K
K
Tashita
A
A
Jomori
T
T
Hotta
N
N
Matsuo
S
S
D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D005260:Female; D005916:Globulins; D005921:Glomerulonephritis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D008070:Lipopolysaccharides; D009844:Oligosaccharides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019087:Selectins / Q000187:drug effects*; D000080506:Sialyl Lewis X Antigen; D013433:Sulfoglycosphingolipids / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000517:prevention & control*
D015815:Cell Adhesion Molecules; D005916:Globulins; D008070:Lipopolysaccharides; D009844:Oligosaccharides; C432088:SKK60037; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D013433:Sulfoglycosphingolipids