Effect of Sepimostat Mesilate on the Development of Glomerulonephritis in NZB/W F1 Mice

ABSTRACT

To determine whether sepimostat mesilate inhibits activation of the complement pathways, and to evaluate the effectiveness of sepimostat mesilate on the development of glomerulonephritis in NZB/W F1 mice.

We used the Wielisa complement functional kit to assess the inhibitory effect of sepimostat mesilate on activation of the complement pathways. Groups of 10 NZB/NZW mice (age 18-22 weeks) were given sepimostat mesilate (200 μg/dose) or glucose (control) five times a week for 5 weeks after onset of proteinuria.

Sepimostat mesilate dose-dependently inhibited the activity of all complement pathways. Administration of sepimostat mesilate after disease onset lowered the levels of blood urea nitrogen (243.2 ± 63.1 versus 120.9 ± 22.1 μg/dl; p<0.0001), C4d (0.244 ± 0.083 versus 0.153 ± 0.059 ng/dl; p=0.011), and delayed the development of proteinuria (0.822 ± 0.116 versus 0.470 ± 0.093 mg/mouse/day; p=0.046) at the end of treatment (22 weeks of age). After discontinuation of administration, blood urea nitrogen, C4d level, and proteinuria rapidly became elevated with no difference between the groups. Eventually, mortality was similar between treated and untreated mice.

Sepimostat mesilate could be a therapeutic option for lupus nephritis.