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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Mechanism of Bradykinin-Induced Ca²⁺ Mobilization in Murine Proximal Tubule Epithelial Cells

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Despite the recognized physiological role of bradykinin (BK) in the kidney in maintaining glomerular and tubule function and its role in pathological states such as endotoxemia, diabetes, and other diseases, relatively little is known about the mechanisms by which BK can impact kidney function. Furthermore, the signaling of BK receptors in the murine nephron has not been fully characterized. The present studies were undertaken to examine BK-stimulated Ca²⁺ signaling using Fura-2 in the murine proximal tubule epithelial cell line TKPTS. BK produced a concentration-dependent rise in intracellular Ca²⁺ ([Ca²⁺])_i (pEC₅₀ = 8.39 ± 0.04). Selective antagonists showed the rise in [Ca²⁺]_i was mediated through B2 receptors. The rise in [Ca²⁺]_i was rapid and reversible and was maximally stimulated at 1 µM (697 ± 70 nM above basal level of 115 ± 6 nM). Studies with thapsigargin and EGTA showed Ca²⁺ mobilization was dependent on two events: release and influx. Both U73122 (1-[6-[[17--3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) [a phospholipase C (PLC) inhibitor] and genistein (a tyrosine kinase inhibitor) partially inhibited BK-stimulated rise in [Ca²⁺]_i. When combined, both agents produced a further decrease, suggesting multiple pathways for PLC activation may be involved. The ability of Ni²⁺ to inhibit influx indicated the activation of a Ca²⁺ release-activated channel (CRAC). Ca²⁺ mobilization did not seem to be affected by cyclic nucleotides or protein kinase C. In summary, the TKPTS murine proximal tubule cell line expresses functional B2 receptors linked to Ca²⁺ mobilization that is dependent on phospholipase C and activation of CRAC.

Address correspondence to: Dr. Philip R. Mayeux, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham St., #611, Little Rock, AR 72205. E-mail: prmayeux{at}uams.edu

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				M. M. Tiwari, K. J. Messer, and P. R. Mayeux Inducible Nitric Oxide Synthase and Apoptosis in Murine Proximal Tubule Epithelial Cells Toxicol. Sci., June 1, 2006; 91(2): 493 - 500. [Abstract] [Full Text] [PDF]