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Am J Physiol Renal Physiol. 2015 Jun 15;308(12):F1409-20. doi: 10.1152/ajprenal.00129.2015. Epub 2015 Apr 29.

Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3.

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InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark;
VA San Diego Healthcare System, San Diego, California;
Department of Medicine, University of Cincinnati, Cincinnati, Ohio; Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio;
The Research Institute of Molecular Pathology, Vienna, Austria;
VA San Diego Healthcare System, San Diego, California; Bastyr University California, San Diego, California; and
VA San Diego Healthcare System, San Diego, California; Department of Medicine, University of California, San Diego, La Jolla, California.


Caffeine is one of the most widely consumed behavioral substances. We have previously shown that caffeine- and theophylline-induced inhibition of renal reabsorption causes diuresis and natriuresis, an effect that requires functional adenosine A1 receptors. In this study, we tested the hypothesis that blocking the Gi protein-coupled adenosine A1 receptor via the nonselective adenosine receptor antagonist caffeine changes Na(+)/H(+) exchanger isoform 3 (NHE3) localization and phosphorylation, resulting in diuresis and natriuresis. We generated tubulus-specific NHE3 knockout mice (Pax8-Cre), where NHE3 abundance in the S1, S2, and S3 segments of the proximal tubule was completely absent or severely reduced (>85%) in the thick ascending limb. Consumption of fluid and food, as well as glomerular filtration rate, were comparable in control or tubulus-specific NHE3 knockout mice under basal conditions, while urinary pH was significantly more alkaline without evidence for metabolic acidosis. Caffeine self-administration increased total fluid and food intake comparably between genotypes, without significant differences in consumption of caffeinated solution. Acute caffeine application via oral gavage elicited a diuresis and natriuresis that was comparable between control and tubulus-specific NHE3 knockout mice. The diuretic and natriuretic response was independent of changes in total NHE3 expression, phosphorylation of serine-552 and serine-605, or apical plasma membrane NHE3 localization. Although caffeine had no clear effect on localization of the basolateral Na(+)/bicarbonate cotransporter NBCe1, pretreatment with DIDS inhibited caffeine-induced diuresis and natriuresis. In summary, NHE3 is not required for caffeine-induced diuresis and natriuresis.


NBCe1; Npt2a; caffeine; fluid homeostasis; natriuresis

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