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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Regulation of Renal Ectophosphodiesterase by Protein Kinase C and Sodium Diet

Center for Clinical Pharmacology, Departments of Pharmacology (E.K.J.) and Medicine (E.K.J., Z.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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 ,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.

Address correspondence to: Dr. Edwin K. Jackson, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Drive, Suite 450, Pittsburgh, PA 15219. E-mail: edj+{at}pitt.edu

This article has been cited by other articles:

				J. Ren, Z. Mi, and E. K. Jackson Assessment of Nerve Stimulation-Induced Release of Purines from Mouse Kidneys by Tandem Mass Spectrometry J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 920 - 926. [Abstract] [Full Text] [PDF]