Increased renal proximal convoluted tubule transport contributes to hypertension in Cyp4a14 knockout mice.
OBJECTIVE
Disrupting the enzyme Cyp4a14 in mice leads to hypertension, which is more severe in the male mice and appears to be due to androgen excess. Because the Cyp4a14 enzyme is located in the proximal tubule of the kidney, we hypothesized that there could be dysregulation of transport in this segment that could contribute to the hypertension.


METHODS
Wild-type (SV/129) mice and mice that had targeted disruption of the Cyp4a14 gene were studied. Proximal convoluted tubules (PCT) from knockout and wild-type mice were dissected and perfused in vitrofor measurement of volume absorption (J(V)). Expression of the sodium-hydrogen exchanger 3 (NHE3), the predominant transporter responsible for sodium transport in this segment, was measured by immunoblot. Renal vascular (afferent arteriole) responses to angiotensin and endothelin were also measured.


RESULTS
PCT volume absorption was elevated in tubules from the Cyp4a14 knockout mice as compared to the wild-type mice. Brush border membrane NHE3 expression was almost 2-fold higher in Cyp4a14 knockout mice than in wild-type mice. No difference was found in the afferent arteriolar response.


CONCLUSIONS
Thus, hypertension in the Cyp4a14 knockout mice appears to be driven by excessive fluid reabsorption in the proximal tubule, which is secondary to overexpression of NHE3.
Quigley
Raymond
R
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 75235-9063, USA. raymond.quigley@utsouthwestern.edu
Chakravarty
Sumana
S
Zhao
Xueying
X
Imig
John D
JD
Capdevila
Jorge H
JH
D000728:Androgens / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D000728:Androgens; C436963:Cyp4a14 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D000072470:Cytochrome P450 Family 4