Tubuloglomerular feedback and renin secretion in NTPDase1/CD39-deficient mice.
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.
Oppermann
Mona
M
National Institute of Digestive and Diabetes and Kidney Diseases, National Institute of Health, 10 Center Drive-MSC 1370, Bethesda, MD 20892, USA.
Friedman
David J
DJ
Faulhaber-Walter
Robert
R
Mizel
Diane
D
Castrop
Hayo
H
Enjyoji
Keiichi
K
Robson
Simon C
SC
Schnermann
Jurgen
J
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D001081:Apyrase / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D007678:Kidney Glomerulus / Q000502:physiology*; D007684:Kidney Tubules / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012083:Renin / Q000097:blood* / Q000378:metabolism; D015398:Signal Transduction
D015703:Antigens, CD; D012083:Renin; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen