Compensation of proximal tubule malabsorption in AQP1-deficient mice without TGF-mediated reduction of GFR.
OBJECTIVE
By crossing aquaporin 1 (AQP1)-/- and adenosine 1 receptor (A1AR)-/- mice, we generated an animal model that combines a proximal tubular absorption defect with absence of tubuloglomerular feedback (TGF) regulation of glomerular filtration rate (GFR). The aim of studies in these animals was to determine whether a TGF-induced reduction of GFR is a prerequisite for preventing potentially fatal fluid losses.


RESULTS
In contrast to AQP1 deficient mice, AQP1/A1AR-/- mice were found to have a normal GFR. TGF responses were abolished in these animals, in contrast to AQP1-/- mice in which TGF responses of single nephron glomerular filtration rate (SNGFR) were left-shifted. Proximal tubule fluid absorption in AQP1/A1AR-/- mice was reduced to levels previously reported for AQP1-/- mice. However, SNGFR was significantly higher in AQP1/A1AR-/- than AQP1-/- mice (10.6 +/- 0.8 nL min(-1) vs. 5.9 +/- 0.7 nL min(-1)). As a consequence of the normal GFR and the reduced proximal reabsorption distal fluid delivery was markedly higher in the double knockout compared with normal or AQP1-/- mice (5.5 +/- 0.5 nL min(-1) vs. 2.35 +/- 0.3 nL min(-1) in AQP1-/-). Despite the approximate doubling of distal fluid and Cl delivery, AQP1/A1AR-/- mice have a normal salt excretion, normal arterial blood pressure, and only a small increase in plasma renin concentration.


CONCLUSIONS
The ability to compensate for proximal tubule malabsorption without a TGF-induced reduction of GFR attests to a remarkable adaptability of distal tubule transport mechanisms.
Hashimoto
S
S
National Institute of Diabetes, and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
Huang
Y
Y
Mizel
D
D
Briggs
J
J
Schnermann
J
J
D000042:Absorption; D000818:Animals; D051398:Aquaporin 1; D020346:Aquaporins / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D005246:Feedback; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007674:Kidney Diseases / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000502:physiology*; D012083:Renin / Q000097:blood; D012964:Sodium / Q000378:metabolism; D015291:Transforming Growth Factors / Q000502:physiology*
C496021:Aqp1 protein, mouse; D020346:Aquaporins; D043682:Receptor, Adenosine A1; D051398:Aquaporin 1; D015291:Transforming Growth Factors; D012964:Sodium; D012083:Renin