Kv1.3 Inhibition Alleviates Diabetic Kidney Injury via Suppression of Inflammation and Fibrosis

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Background: Kv1.3, a voltage-gated potassium ion channel, plays a crucial role in energy homeostasis through the regulation of proliferation and apoptosis. Inhibition of the Kv1.3 channel has shown beneficial effects in a range of diseases such as neuroinflammatory disorders, autoimmune diseases, and cancer. Previously, we have shown that Kv1.3 was significantly upregulated in diabetic mice kidneys, indicating an important role of Kv1.3 in diabetic kidney disease (DKD). HsTX1[R14A] is a potent selective inhibitor of this channel, with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold. However, the renoprotective effect of HsTX1[R14A] in DKD has not been explored. This study aims to investigate the efficacy of Kv1.3 inhibitor HsTX1[R14A] in a mouse model of obesity-induced DKD. Methods: C57BL/6 mice were fed with a high-fat diet (HFD) for 12 weeks. Diabetic mice then received subcutaneous injections of a control peptide, or low/high dose of HsTX1[R14A] every other day for another 12 weeks. Renal function, as well as fibrotic and inflammatory markers, were then assessed. Results: The level of 24h urinary albumin and the urinary albumin-creatinine ratio were significantly elevated in the diabetic mice that received control peptide, compared to the non-diabetic controls (P< 0.01), and these levels were significantly reduced by HsTX1[R14A] treatment at both dosages (P<0.05). Moreover, qRT-PCR results showed that the treatment of HsTX1[R14A] at the higher dose, but not the low dose, significantly reversed the HFD-induced overexpression of fibrotic marker collagen 1 and inflammatory marker tumour necrosis factor-α in diabetic mice (P<0.05), when compared with diabetic mice that received the control peptide. Conclusion: The Kv1.3 inhibitor HsTX1[R14A] shows promising therapeutic effects in diabetic kidney disease. Funding: Government Support – Non-U.S.

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