Therapeutic potential of voltage-dependent potassium channel subtype 1.3 blockade in alleviating macrophage-related renal inflammation and fibrogenesis.

Macrophage polarization and infiltration are notable characteristics of kidney injury and fibrosis. Although voltage-dependent potassium channel subtype (Kv) 1.3 is involved in macrophage-induced inflammation, its precise mechanism has not been elucidated. Therefore, this study aimed to explore the role of Kv1.3 in renal injury and macrophage polarization. Herein, mouse models of kidney injury were established through unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI). For intervention, a selective Kv1.3 blocker, margatoxin (MgTx), was administered intraperitoneally. Blood and kidney samples were collected on days 3 and 7 following UUO surgery to evaluate renal Kv1.3 expression, kidney injury, macrophage polarization changes, cytokine levels, phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). Kidney samples were also collected 24 h after IRI to assess kidney injury and evaluate renal Kv1.3 expression, as well as the phosphorylation levels of ERK and NF-κB. Histological analysis of MgTx-treated UUO and IRI mice revealed that Kv1.3 inhibition markedly alleviated renal damage induced by UUO and IRI, substantially reducing the levels of myofibroblast markers, specifically α-smooth muscle actin and transforming growth factor-β1. In UUO mice, Kv1.3 expression and proportions of monocyte-derived cells in peripheral blood and M1 macrophages notably increased but reversed after MgTx treatment, indicating diminished macrophage infiltration. Additionally, MgTx treatment downregulated various M1-related proinflammatory markers, including tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin (IL)-1β, and upregulated M2-associated markers such as IL-10, arginase-1, and CD206. Moreover, Kv1.3 overexpression in THP-1 cells upregulated M1 macrophage markers and proinflammatory cytokines, enhanced their migratory ability. This indicates an increased polarization towards the M1 phenotype, which correlates with impaired renal tubular epithelial cells. Notably, Kv1.3 upregulation both in vivo and in vitro led to increased phosphorylation of ERK and NF-κB, possibly promoting M1 macrophage polarization. This study establishes Kv1.3 as a pivotal regulator of renal fibrosis and macrophage polarization, showing that its inhibition leads to reduced infiltration and migration of M1 macrophages, mitigation of renal injury via suppression of ERK/NF-κB signaling. Altogether, these findings suggest the potential of Kv1.3 as a promising therapeutic target for renal fibrosis.