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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/F965    most recent 00603.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Oppermann, M. Articles by Schnermann, J. PubMed PubMed Citation Articles by Oppermann, M. Articles by Schnermann, J.

Tubuloglomerular feedback and renin secretion in NTPDase1/CD39-deficient mice

¹National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and ²Beth Israel Deaconess Medical Center, Boston, Massachusetts

Submitted 20 January 2007 ; accepted in final form 5 February 2008

Studies in mice with null mutations of adenosine 1 receptor or ecto-5'-nucleotidase genes suggest a critical role of adenosine and its precursor 5'-AMP in tubulovascular signaling. To assess whether the source of juxtaglomerular nucleotides can be traced back to ATP dephosphorylation, experiments were performed in mice with a deficiency in NTPDase1/CD39, an ecto-ATPase catalyzing the formation of AMP from ATP and ADP. Urine osmolarity and glomerular filtration rate (GFR) were indistinguishable between NTPDase1/CD39^–/– and wild-type (WT) mice. Maximum tubuloglomerular feedback (TGF) responses, as determined by proximal tubular stop flow pressure measurements, were reduced in NTPDase1/CD39^–/– mice compared with controls (4.2 ± 0.9 vs. 10.5 ± 1.2 mmHg, respectively; P = 0.0002). Residual TGF responses gradually diminished after repeated changes in tubular perfusion flow averaging 2.9 ± 0.9 (on response) and 3.5 ± 1.1 (off response) mmHg after the second and 2.2 ± 0.5 (on response) and 1.5 ± 0.8 (off response) mmHg after the third challenge, whereas no fading of TGF responsiveness was observed in WT mice. Macula densa-dependent and pressure-dependent inhibition of renin secretion, as assessed by acute salt loading and phenylephrine injection, respectively, were intact in NTPDase1/CD39-deficient mice. In summary, NTPDase1/CD39-deficient mice showed a markedly compromised TGF regulation of GFR. These data support the concept of an extracellular dephosphorylation cascade during tubular-vascular signal transmission in the juxtaglomerular apparatus that is initiated by a regulated release of ATP from macula densa cells and results in adenosine-mediated afferent arteriole constriction.

adenosine 5'-triphosphate; CD73; stop flow pressure; phenylephrine; adenosine