Delayed Rectifier K⁺-Channel Is a Novel Therapeutic Target for Interstitial Renal Fibrosis in Rats with Unilateral Ureteral Obstruction

Abstract

Background Delayed rectifier K+-channel, Kv1.3, is most predominantly expressed in T-lymphocytes and macrophages. In such leukocytes, Kv1.3-channels play pivotal roles in the activation and proliferation of cells, promoting cellular immunity. Since leukocyte-derived cytokines stimulate fibroblasts to produce collagen fibers in inflamed kidneys, Kv1.3-channels expressed in leukocytes would contribute to the progression of tubulointerstitial renal fibrosis. Methods Male Sprague-Dawley rats that underwent unilateral ureteral obstruction (UUO) were used at 1, 2, or 3 weeks after the operation. We examined the histological features of the kidneys and the leukocyte expression of Kv1.3-channels. We also examined the therapeutic effects of a selective channel inhibitor, margatoxin, on the progression of renal fibrosis and the proliferation of leukocytes within the cortical interstitium. Results In rat kidneys with UUO, progression of renal fibrosis and the infiltration of leukocytes became most prominent at 3 weeks after the operation, when Kv1.3-channels were overexpressed in proliferating leukocytes. In the cortical interstitium of margatoxin-treated UUO rat kidneys, immunohistochemistry revealed reduced expression of fibrosis markers. Additionally, margatoxin significantly decreased the numbers of leukocytes and suppressed their proliferation. Conclusions This study clearly demonstrated that the numbers of T-lymphocytes and macrophages were markedly increased in UUO rat kidneys with longer postobstructive days. The overexpression of Kv1.3-channels in leukocytes was thought to be responsible for the proliferation of these cells and the progression of renal fibrosis. This study strongly suggested the therapeutic usefulness of targeting lymphocyte Kv1.3-channels in the treatment of renal fibrosis.

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“…We have demonstrated in several animal studies that the overexpression of Kv1.3-channels in T-lymphocytes and macrophages is strongly associated with their over-activation and the progression of renal fibrosis (12,13). In these studies, margatoxin, a selective Kv1.3channel inhibitor, actually suppressed the activity of the leukocytes and slowed the progression of renal fibrosis.…”

Ion channels as a therapeutic target for renal fibrosis

“…Importantly, inhibition of Kv1.3 channels using the selective blocker margatoxin significantly inhibited renal lymphocyte proliferation and ameliorated the progression of renal fibrosis. Their team further demonstrated the effectiveness of targeting lymphocyte Kv1.3 channels in the treatment of renal fibrosis using the UUO mouse model ( Abe et al, 2019 ). Furthermore, stimulation with TGF-β significantly induced an increase in Kv1.3 density and outward K + current amplitude, and the Kv1.3 channel inhibitor regulated the expression of the TGF-β in mouse microglia ( Schilling et al, 2000 ), hypothesizing that Kv1.3 channel inhibitors have a similar mechanism to alleviate renal fibrosis by regulating the expression of the cytokine TGF-β.…”

Lymphocytes: Versatile Participants in Acute Kidney Injury and Progression to Chronic Kidney Disease

“…Besides that, as one of the inhibitors of delayed rectifier K + -channel, Kv1.3 like margatoxin (Abe et al, 2019 ) and YM58343/BTP2 (Mehrotra et al, 2019 ) were expressed on T lymphocytes, and also found to acute injury and chronic fibrosis in rat kidney. T cell infiltration was decreased by a wingless-type (Wnt)/β-catenin pathway inhibitor, ICG-001, which therefore prevented CKD in a 5/6 nephrectomy model (Xiao et al, 2019 ).…”