Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel.
Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10-/- mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease.
Nakagawa
Kiyoshi
K
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Holla
Vijaykumar R
VR
Wei
Yuan
Y
Wang
Wen-Hui
WH
Gatica
Arnaldo
A
Wei
Shouzou
S
Mei
Shaojun
S
Miller
Crystal M
CM
Cha
Dae Ryong
DR
Price
Edward
E
Zent
Roy
R
Pozzi
Ambra
A
Breyer
Matthew D
MD
Guan
Youfei
Y
Falck
John R
JR
Waterman
Michael R
MR
Capdevila
Jorge H
JH
D000584:Amiloride / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004594:Electrophysiology; D053503:Epithelial Sodium Channels; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011743:Pyrimidines / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D012982:Sodium, Dietary
D001095:Arachidonic Acids; C512110:Cyp4a10 protein, mouse; D053503:Epithelial Sodium Channels; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012982:Sodium, Dietary; D000584:Amiloride; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; C492667:Cyp2c23 protein, mouse; D000072467:Cytochrome P450 Family 2