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 Ca(2+) 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.

• Authors: Itsuro Kazama, Asuka Baba, Mitsunobu Matsubara, Yasuhiro Endo, Hiroaki Toyama, Yutaka Ejima
• Journal: Nephron. Experimental nephrology (Nephron Exp Nephrol) Vol. 128 Issue 1-2 Pg. 67-79 ( 2014) ISSN: 1660-2129 [Electronic] Switzerland
• PMID: 25358915 (Publication Type: Journal Article)
• Copyright: © 2014 S. Karger AG, Basel.

Chemical References

• Calcium Channel Blockers
• Cytokines
• Dihydropyridines
• Kv1.3 Potassium Channel
• benidipine
• Creatinine

Topics

• Animals
• Blood Urea Nitrogen
• Calcium Channel Blockers (pharmacology, therapeutic use)
• Cell Proliferation (drug effects)
• Creatinine (blood)
• Cytokines (metabolism)
• Dihydropyridines (pharmacology, therapeutic use)
• Disease Models, Animal
• Disease Progression
• Fibrosis (prevention & control)
• Kidney (metabolism, pathology, surgery)
• Kidney Failure, Chronic (drug therapy, etiology, pathology)
• Kv1.3 Potassium Channel (metabolism)
• Leukocytes (drug effects, metabolism, pathology)
• Male
• Nephrectomy (adverse effects)
• Rats
• Rats, Sprague-Dawley