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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Manish M. Tiwari, Paul L. Prather and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics May 2005, 313 (2) 798-805; DOI: https://doi.org/10.1124/jpet.104.080408
Manish M. Tiwari
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Paul L. Prather
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Philip R. Mayeux
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Abstract

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-β-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.

Footnotes

  • This research was supported by funds from the University of Arkansas for Medical Sciences Graduate Student Research Fund (to M.M.T.).

  • doi:10.1124/jpet.104.080408.

  • ABBREVIATIONS: BK, bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg); d-Arg0[Hyp3, d-Phe7]-BK, d-Arg-Arg-Pro-Hydroxy-Pro-Gly-Phe-Ser-d-Phe-Phe-Arg;d-Arg0[Hyp3,Thi5,8,d-Phe7]-BK,d-Arg-Arg-Pro-Hydroxy-Pro-Gly-β-(2-Thienyl)Ala-Ser-d-Phe-β-(2-Thienyl)Ala-Arg;des-Arg9[Leu8]-BK,Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu; des-Arg9-BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe; B2, bradykinin receptor subtype 2; TMB-8, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride; BIM, bisindolylmaleimide I hydrochloride (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide, HCl); H89, N-[2-p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; KT5823, C29H25N3O5; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; U73122, 1-[6-[[17-β-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione; U73343, 1-[6-[[17-β-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidinedione; PMA, phorbol 12-myristate 13-acetate; RT-PCR, reverse transcription-polymerase chain reaction; PCR, polymerase chain reaction; bp, base pair; PI3K, phosphoinositide 3-kinase; IP3, inositol 1,4,5-trisphosphate; CRAC, calcium release-activated channel; PLC, phospholipase C; PKA, protein kinase A; PKG, protein kinase G; PKC, protein kinase C; MDCK, Madin-Darby canine kidney.

    • Received November 8, 2004.
    • Accepted January 20, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Manish M. Tiwari, Paul L. Prather and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics May 1, 2005, 313 (2) 798-805; DOI: https://doi.org/10.1124/jpet.104.080408

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Manish M. Tiwari, Paul L. Prather and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics May 1, 2005, 313 (2) 798-805; DOI: https://doi.org/10.1124/jpet.104.080408
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