期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 307, 期 7, 页码 F833-F843出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00141.2014
关键词
angiotensin II; angiotensin II type 2 receptor; cortical collecting duct; renal outer medullary potassium channel; protein kinase A
资金
- American Heart Association Scientist Development [0530092N]
- NIH [DK-47402, DK-38470, DK-51391, P30-DK-079307]
- Department of Veterans Affairs Merit Review [1I01BX000388]
The kidney adjusts K+ excretion to match intake in part by regulation of the activity of apical K+ secretory channels, including renal outer medullary K+ (ROMK)-like K+ channels, in the cortical collecting duct (CCD). ANG II inhibits ROMK channels via the ANG II type 1 receptor (AT(1)R) during dietary K+ restriction. Because AT(1)Rs and ANG II type 2 receptors (AT(2)Rs) generally function in an antagonistic manner, we sought to characterize the regulation of ROMK channels by the AT(2)R. Patchclamp experiments revealed that ANG II increased ROMK channel activity in CCDs isolated from high-K+ (HK)-fed but not normal K+ (NK)-fed rats. This response was blocked by PD-123319, an AT(2)R antagonist, but not by losartan, an AT(1)R antagonist, and was mimicked by the AT(2)R agonist CGP-42112. Nitric oxide (NO) synthase is present in CCD cells that express ROMK channels. Blockade of NO synthase with N-nitro-L-arginine methyl ester and free NO with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt completely abolished ANG II-stimulated ROMK channel activity. NO enhances the synthesis of cGMP, which inhibits phosphodiesterases (PDEs) that normally degrade cAMP; cAMP increases ROMK channel activity. Pretreatment of CCDs with IBMX, a broad-spectrum PDE inhibitor, or cilostamide, a PDE3 inhibitor, abolished the stimulatory effect of ANG II on ROMK channels. Furthermore, PKA inhibitor peptide, but not an activator of the exchange protein directly activated by cAMP (Epac), also prevented the stimulatory effect of ANG II. We conclude that ANG II acts at the AT(2)R to stimulate ROMK channel activity in CCDs from HK-fed rats, a response opposite to that mediated by the AT(1)R in dietary K+-restricted animals, via a NO/cGMP pathway linked to a cAMPPKA-PKA pathway.
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