Roles of lymphocyte kv1.3-channels in the pathogenesis of renal diseases and novel therapeutic implications of targeting the channels.

Itsuro Kazama

doi:10.1155/2015/436572

Abstract

Delayed rectifier K+-channels (Kv1.3) are predominantly expressed in T lymphocytes. Based on patch-clamp studies, the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. Using selective channel inhibitors in experimental animal models, in vivo studies then revealed the clinically relevant relationship between the channel expression and the pathogenesis of autoimmune diseases. In renal diseases, in which “chronic inflammation” or “the overstimulation of cellular immunity” is responsible for the pathogenesis, the overexpression of Kv1.3-channels in lymphocytes promotes their cellular proliferation and thus contributes to the progression of tubulointerstitial fibrosis. We recently demonstrated that benidipine, a potent dihydropyridine calcium channel blocker, which also strongly and persistently inhibits the lymphocyte Kv1.3-channel currents, suppressed the proliferation of kidney lymphocytes and actually ameliorated the progression of renal fibrosis. Based on the recent in vitro evidence that revealed the pharmacological properties of the channels, the most recent studies have revealed novel therapeutic implications of targeting the lymphocyte Kv1.3-channels for the treatment of renal diseases.

Highlights

T lymphocytes predominantly express delayed rectifier K+channels (Kv1.3) in their plasma membranes [1,2,3]
Previous studies demonstrated the involvement of inflammatory leukocytes, such as T lymphocytes, macrophages, and mast cells, in the pathogenesis of renal diseases, such as glomerulonephritis, chronic kidney disease (CKD), or tubulointerstitial fibrosis [7,8,9,10,11]
As an extension of these studies, our studies further suggested that targeting the Kv1.3channels overexpressed in leukocytes would be useful for the treatment of renal fibrosis in advanced chronic renal failure (CRF) [11, 34]

Summary

Introduction

T lymphocytes predominantly express delayed rectifier K+channels (Kv1.3) in their plasma membranes [1,2,3]. Recent patch-clamp studies, including ours, have shown that commonly used drugs, such as calcium channel blockers (CCBs) [18, 19], macrolide antibiotics, and HMG-CoA reductase inhibitors, effectively suppress the Kv1.3-channel currents in lymphocytes [20, 21]. Such studies suggested the therapeutic efficacy of these drugs for the treatment of renal diseases, in which “chronic inflammation” or “the overstimulation of cellular immunity” is responsible for the pathogenesis [22]. The recent in vitro and in vivo evidence that revealed the pharmacological properties of the channels, this review focuses on the novel therapeutic implications of targeting the channels for the treatment of renal diseases

Increased Numbers of Leukocytes in Rat Kidneys with Renal Diseases

Conclusions and Perspectives