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.