Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 9, Pages 6455-6462Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M607477200
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Funding
- NCI NIH HHS [R24 CA095823, 5R24 CA095823-04] Funding Source: Medline
- NIDDK NIH HHS [R01 DK047402, DK38470, DK51391, R01 DK047402-13, DK47402] Funding Source: Medline
- PHS HHS [1 S10 RRO 9145-01] Funding Source: Medline
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Base-line urinary potassium secretion in the distal nephron is mediated by small conductance rat outer medullary K (ROMK)like channels. We used the patch clamp technique applied to split-open cortical collecting ducts (CCDs) isolated from rats fed a normal potassium (NK) or low potassium (LK) diet to test the hypothesis that AngII directly inhibits ROMK channel activity. We found that AngII inhibited ROMK channel activity in LK but not NK rats in a dose-dependent manner. The AngII-induced reduction in channel activity was mediated by AT 1 receptor (AT1R) binding, because pretreatment of CCDs with losartan but not PD123319 AT1. and AT2 receptor antagonists, respectively, blocked the response. Pretreatment of CCDs with U73122 and calphostin C, inhibitors of phospholipase C (PLC) and protein kinase C (PKC), respectively, abolished the AngII-induced decrease in ROMK channel activity, confirming a role of the PLC-PKC pathway in this response. Studies by others suggest that AngII stimulates an Src family protein-tyrosine kinase (PTK) via PKC-NADPH oxidase. PTK has been shown to regulate the ROMK channel. Inhibition of NADPH oxidase with diphenyliodonium abolished the inhibitory effect of AngII or the PKC activator phorbol 12-myristate 13-acetate on ROMK channels. Suppression of PTK by herbimycin A significantly attenuated the inhibitory effect of AngII on ROMK channel activity. We conclude that AngII inhibits ROMK channel activity through PKC-, NADPH oxidase-, and PTK-dependent pathways under conditions of dietary potassium restriction.
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