Effect of Sepimostat Mesilate on the Development of Glomerulonephritis in NZB/W F1 Mice
Hiroshi Watanabe*, Shuzo Sato, Rie Saito, Haruyo Iwadate, Hiroko Kobayashi, Hiromasa Ohira
Identifiers and Pagination:Year: 2011
First Page: 11
Last Page: 15
Publisher Id: TOIJ-4-11
Article History:Received Date: 3/9/2010
Revision Received Date: 1/11/2010
Acceptance Date: 9/12/2010
Electronic publication date: 2/2/2011
Collection year: 2011
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.