RT Journal Article
SR Electronic
T1 Regulation of Renal Ectophosphodiesterase by Protein Kinase C and Sodium Diet
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 210
OP 216
DO 10.1124/jpet.107.134445
VO 325
IS 1
A1 Edwin K. Jackson
A1 Zaichuan Mi
YR 2008
UL http://jpet.aspetjournals.org/content/325/1/210.abstract
AB Kidneys metabolize arterial cAMP to adenosine by the sequential actions of ectophosphodiesterase (cAMP → AMP) and ecto-5′-nucleotidase (AMP → adenosine). In this study, we demonstrated that etheno-AMP (fluorescent AMP analog) is nearly completely converted to etheno-adenosine during a single pass through the isolated, perfused rat kidney indicating that ecto-5′-nucleotidase is not rate limiting. Therefore, we examined the regulation of ectophosphodiesterase. In 17 control kidneys pretreated with α,β-methylene-adenosine-5′-diphosphate (inhibitor of ecto-5′-nucleotidase to prevent AMP metabolism; 100 μM), addition of cAMP (10 μM) to the perfusate increased renal venous AMP from 0.6 ± 0.2 to 3.5 ± 0.5 nmol/min/g. Pretreatment of kidneys with phorbol 12-myristate 13-acetate (protein kinase C activator; 7.5 nM) increased renal vascular resistance and significantly augmented the cAMP-induced increase in renal venous AMP (from 0.8 ± 0.2 to 5.2 ± 0.7 nmol/min/g with cAMP). Pretreatment of kidneys with bisindolymaleimide I (protein kinase C inhibitor; 3 μM) abrogated the effects of phorbol 12-myristate 13-acetate on both renovascular resistance and cAMP conversion to AMP. Compared with kidneys from rats fed a high-sodium diet (3.15%) for 1 week, in kidneys from rats fed a low-sodium diet (0.03%) the conversion of cAMP to AMP was attenuated (high sodium, from 1.0 ± 0.1 to 4.6 ± 0.4 nmol/min/g with cAMP; low sodium, from 0.5 ± 0.04 to 2.6 ± 0.04 nmol/min/g with cAMP). We conclude that the renal vasculature efficiently converts AMP to adenosine and that metabolism of cAMP to AMP is rate limiting and regulated acutely by protein kinase C and chronically by sodium intake. The American Society for Pharmacology and Experimental Therapeutics