Voltage-gated potassium channel Kv1.3 blocker as a potential treatment for rat anti-glomerular basement membrane glomerulonephritis

Abstract

The voltage-gated potassium channel Kv1.3 has been recently identified as a molecular target that allows the selective pharmacological suppression of effector memory T cells (T(EM)) without affecting the function of naïve T cells (T(N)) and central memory T cells (T(CM)). We found that Kv1.3 was expressed on glomeruli and some tubules in rats with anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). A flow cytometry analysis using kidney cells revealed that most of the CD4(+) T cells and some of the CD8(+) T cells had the T(EM) phenotype (CD45RC(-)CD62L(-)). Double immunofluorescence staining using mononuclear cell suspensions isolated from anti-GBM GN kidney showed that Kv1.3 was expressed on T cells and some macrophages. We therefore investigated whether the Kv1.3 blocker Psora-4 can be used to treat anti-GBM GN. Rats that had been given an injection of rabbit anti-rat GBM antibody were also injected with Psora-4 or the vehicle intraperitoneally. Rats given Psora-4 showed less proteinuria and fewer crescentic glomeruli than rats given the vehicle. These results suggest that T(EM) and some macrophages expressing Kv1.3 channels play a critical role in the pathogenesis of crescentic GN and that Psora-4 will be useful for the treatment of rapidly progressive glomerulonephritis.

Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease

“…In addition, specific Kv1.3 inhibitors have been found to be effective in numerous animal models of inflammation including chronic relapse-remitting experimental autoimmune encephalomyelitis (CR-EAE) and adoptive EAE (Beeton et al, 2005(Beeton et al, , 2006, pristane-induced arthritis (PIA) (Beeton et al, 2006), the delayed-type hypersensitivity (DTH) reaction (Koo et al, 1997;Beeton et al, 2005;Matheu et al, 2008), allergic contact dermatitis (Azam et al, 2007), allogeneic kidney transplant (Grgic et al, 2009), spontaneous autoimmune diabetes (Beeton et al, 2006), vascular neointima hyperplasia (Cheong et al, 2011), antiglomerular basement membrane glomerulonephritis (Hyodo et al, 2010), and psoriasis (Gilhar et al, 2011). For these reasons, numerous groups have focused on developing specific and potent inhibitors of the Kv1.3 channel for the treatment of inflammation and autoimmune disease Chandy 2009, Rangaraju et al, 2009).…”

Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases

“…Based on these findings, the authors also demonstrated the therapeutic efficacy of a Kv1.3-channel inhibitor, PAP-1, in dextran sodium sulfate (DSS)-induced rat models of ulcerative colitis [90] (Table 1). In experimental animal models of renal diseases, including renal allograft rejection [91] and acute glomerulonephritis [92], immunosuppression by the blockade of lymphocyte Kv1.3-channels actually prevented or ameliorated the progression of the diseases. Using selective Kv1.3-channel inhibitors, such as ShK and Psora-4, therapeutically [91,92], these studies demonstrated the contribution of the channels to the pathogenesis of renal diseases (Table 1).…”

“…In experimental animal models of renal diseases, including renal allograft rejection [91] and acute glomerulonephritis [92], immunosuppression by the blockade of lymphocyte Kv1.3-channels actually prevented or ameliorated the progression of the diseases. Using selective Kv1.3-channel inhibitors, such as ShK and Psora-4, therapeutically [91,92], these studies demonstrated the contribution of the channels to the pathogenesis of renal diseases (Table 1). Recently, using a rat model with advanced chronic renal failure (CRF), we demonstrated for the first time that Kv1.3-channels were overexpressed in proliferating leukocytes within fibrotic kidneys [61].…”

“…Modified from Ref. [31] autoimmune disorders [63,81,[83][84][85][86][87][88][89][90], renal diseases [61,91,92], and respiratory disease [93,96,123] (Table 1). However, the therapeutic efficacies of these compounds were for the most part observed only in experimental animal models.…”

Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation - a pilot study

“…The central memory T cell (Tcm) population (CD45RC-CCR7+ [21,36]) was increased in graft infiltrating CD4+ and CD8+ T cells after i.p. and local correolide C treatment as compared with controls (Fig.…”