title: Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice.
abstract: Accumulating evidence from murine studies suggests that the RhoA/ROCK pathway plays an important role in the development of autoimmune disorders. We previously demonstrated that ROCK inhibition ameliorates disease in MRL/lpr mice, a spontaneous model of lupus. This study aimed to explore the protective effects of the ROCK inhibitor fasudil in a distinct model of lupus, NZB/W F1 female mice, to assess the broad applicability of ROCK inhibition for the treatment of lupus. NZB/W F1 female mice were administered fasudil continuously in their drinking water starting at 18 or 24 weeks of age up until 44 weeks of age, or remained untreated. Fasudil treatment significantly improved survival and decreased proteinuria, particularly when treatment was started at 18 weeks. There was also a significant decrease in serum anti-dsDNA autoantibody production, glomerular IgG and C3 deposition, and glomerulonephritis. Analysis of the splenic lymphocyte compartment revealed reduced effector/memory CD4(+) T cell and plasma cell numbers in fasudil treated mice while the frequency of other B cell and T cell subsets was unchanged. These results thus indicate that fasudil can ameliorate disease in NZB/W F1 female mice, suggesting that ROCK inhibition might be broadly effective for the treatment of lupus.
authors.affiliation: Autoimmunity and Inflammation Research Program, Hospital for Special Surgery, New York, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Stirzaker
authors.forename: P S
authors.initials: PS
authors.lastname: Biswas
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.forename: L
authors.initials: L
authors.lastname: Song
authors.forename: G
authors.initials: G
authors.lastname: Bhagat
authors.forename: A B
authors.initials: AB
authors.lastname: Pernis
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005921:Glomerulonephritis / Q000517:prevention & control; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D008817:Mice, Mutant Strains; D011507:Proteinuria / Q000517:prevention & control; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D004791:Enzyme Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil