Benidipine Suppresses in situ Proliferation of Leukocytes and Slows the Progression of Renal Fibrosis in Rat Kidneys with Advanced Chronic Renal Failure

Abstract

Background/Aims: Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K⁺ channels (Kv1.3) in their plasma membranes. In our previous study, the overexpression of these channels in leukocytes was strongly associated with their proliferation in kidneys and the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). Since benidipine, a long-acting 1,4-dihydropyridine Ca²⁺ channel blocker, is also highly potent as a Kv1.3 channel inhibitor, it could exert therapeutic efficacy in advanced CRF. Methods: Male Sprague-Dawley rats that underwent 5/6 nephrectomy followed by a 14-week recovery period were used as the model of advanced CRF. Benidipine hydrochloride (5 mg/kg) was started at 8 weeks after nephrectomy and orally administered daily for 6 weeks. The histopathological features of the kidneys were examined in vehicle-treated and benidipine-treated CRF rat kidneys. Cellular proliferation of leukocytes and the cortical expression of proinflammatory cytokines were also examined. Results: In CRF rat kidneys, Kv1.3 channels began to be overexpressed in leukocytes as early as 8 weeks after nephrectomy. In the cortical interstitium of benidipine-treated CRF rat kidneys, both immunohistochemistry and real-time PCR demonstrated decreased expression of fibrotic markers. Benidipine treatment significantly reduced the number of proliferating leukocytes within the cortical interstitium and decreased the expression of cell cycle markers and proinflammatory cytokines. Conclusion: This study demonstrated for the first time that benidipine slowed the progression of renal fibrosis in rat kidneys with advanced CRF. Kv1.3 channels overexpressed in leukocytes were thought to be the most likely therapeutic targets of benidipine in decreasing the number of proliferating leukocytes and repressing the production of inflammatory cytokines.

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

“…Additionally, the persistent effect of benidipine in decreasing the channel currents suggested its longer duration of action in thymocytes, as previously demonstrated in cardiomyocytes [153] and isolated coronary arteries [154]. In our recent study using a rat model of advanced CRF [98], benidipine, by suppressing the in situ proliferation of kidney lymphocytes, actually repressed their cytokine production, and thus ameliorated the progression of renal fibrosis. In respiratory diseases, such as asthma and lung carcinoma, verapamil, which also totally and almost irreversibly inhibited the Kv1.3-channel currents in our most recent patch-clamp study [59] ( Table 2), has actually been shown to be useful in the prophylaxis and treatment of the diseases [155][156][157][158].…”

“…As we recently demonstrated in kidneys with chronic inflammation [61,98], the activity of T lymphocytes and their in situ proliferation within the peripheral organs are largely dependent on the activity of the Kv1.3-channels and their expression level. Therefore, in this context, it is most likely that the channels are also over-activated or overexpressed in T lymphocytes in these acute or chronic respiratory diseases.…”

Mast cell involvement in the progression of peritoneal fibrosis in rats with chronic renal failure

“…Rats with 5/6 nephrectomy and 8‐week recovery periods were used as the model of CRF in the present study. Subtotal nephrectomy was performed in male Sprague–Dawley rats weighing 150–180 g (Japan SLC, Shizuoka, Japan) as described in our previous studies . Briefly, the upper third and lower third of the right kidney were ligated to induce infarction.…”

Lymphocyte Kv1.3-channels in the pathogenesis of chronic obstructive pulmonary disease: novel therapeutic implications of targeting the channels by commonly used drugs

“…Additionally, in our series of patch-clamp studies, commonly used drugs, such as calcium channel blockers (CCBs) [25, 27], macrolide antibiotics [24], HMG-CoA reductase inhibitors (statins) [26] and nonsteroidal anti-inflammatory drugs (NSAIDs) [23], also effectively inhibited the Kv1.3-channel currents in thymus-derived murine lymphocytes. Of note, benidipine, one of the dihydropyridine-type CCBs, which most strongly and persistently inhibited the channel currents [25], actually suppressed the proliferation of kidney lymphocytes, and thus ameliorated the progression of renal fibrosis [47]. In this regard, in addition to using the previously developed selective blockers for the channels [48–50], the use of CCBs, macrolide antibiotics or statins could also potentially be useful in the treatment of COPD (Fig.…”