Abstract
Objective : The Rho family of small GTPases is involved in cell cytoskeletal rearrangement. RhoA has an important role in the podocyte structure, especially in stress fiber formation. RhoA is activated by several G protein-coupled receptors, including angiotensin II type 1 receptor (AT1R). Therefore, the roles of RhoA have been discussed in angiotensin II (Ang II) -induced signaling pathways. In addition, several reports indicated that the local renin-angiotensin system (RAS) is involved in podocyte injury that would induce glomerular crescentic formation. We have previously demonstrated that crescentic glomerular injury in Fc receptor (FcR)-deficient mice [γ (-/-)] with an anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN) was markedly suppressed by AT1R antagonist. Indeed, anti-GBM GN was completely attenuated in bone marrow chimeras between γ (-/-) and AT1R (-/-) mice. Accordingly, we hypothesized that the RhoA kinase inhibitor, fasudil, may attenuate AT1R- dependent crescentic glomerulonephritis.
Materials and Methods : We induced anti-GBM GN in γ (-/-) mice with or without fasudil (10mg/ kg i.p.) and analyzed the disease course. In addition, we stimulated cultured podocytes by Ang II with or without fasudil pretreatment. Then we analyzed the mRNA expression of nephrin.
Results : Fasudil markedly attenuated proteinuria (p<0.01) and hematuria (p<0.01) with prevention of sclerotic change (p<0.01) and crescentic formation (p<0.01). Moreover, WT-1 and nephrin expressions in podocytes were conserved only in the fasudil treatment group. An in vitro study with cultured podocytes further confirmed that fasudil preserves nephrin expression under Ang II stimulation.
Conclusion : Our present findings demonstrated that fasudil prevents AT1R-dependent crescentic formation in and-GBM GN via podocyte protection.
