Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice

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. Lupus (2012) 21, 656-661.