Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel

Abstract

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. IntroductionPrevalence, complexity, and multiple medical and socioeconomic consequences make hypertension a major health challenge for most of the Western world (1). While environmental factors and coexist ing conditions play a role in the development and progression of hypertension, segregation and linkage analyses indicate that mul tiple genetic factors contribute to its complex etiology (2-7). Fur thermore, clinical studies show that the cardiovascular and renal morbidity and mortality resulting from hypertension are markedly reduced by timely diagnosis and early clinical intervention (1). As the kidneys play a central role in the control of body salt and fluid balance, they are frequent targets for the treatment of hypertension, especially those forms sensitive to dietary salt (2-5). However, since the molecular basis of prevalent forms of the disease remains uncer tain, its early diagnosis and treatment are largely symptomatic. It is expected that the identification of novel pathways/genes involved in blood pressure variations (3, 6, 7) will lead to new therapeutic targets and to improved diagnosis and prevention. Indeed, early detection and treatment are urgently needed to prevent the dangerous and profound consequences of untreated chronic hypertension.The metabolism of endogenous arachidonic acid (AA) to epoxy eicosatrienoic acids (EETs) and 20hydroxyeicosatetraenoic acid

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

“…Roles for these enzymes in BP regulation were indicated by the demonstration that their kidney expression was dietary salt-sensitive (21,26,33) and that hypertensive salt-sensitive Dahl rats showed reduced renal CYP2C23 epoxygenase expression and EET biosynthesis (33). However, the complexity of the Dahl rat salt-sensitive genotype precluded unequivocal evaluations of roles for the CYP2C23 gene in salt-sensitive hypertension (33).…”

“…Blood Pressure Measurements-The systolic BPs of conscious 12-20-week-old mice (Ն15 animals/group) were measured between 9 and 11 a.m. by means of a Micro-Renthane tapered catheter (300 -500-m outer diameter) inserted into the right carotid artery as described (26) and connected to a remote pressure sensor. 1-2 days after surgery, the animals were allowed to become familiar with the environment, and their BP was monitored for at least 40 min at an ambient temperature of 23°C.…”

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

“…These same product ions were also used for the deuterated internal standards. Quantifications were performed using the ratio of the area of the DHET peaks compared to the area of the corresponding deuterated DHET peaks (Capdevila et al ., 1991; Nakagawa et al ., 2006). …”

Altered Release of Cytochrome P450 Metabolites of Arachidonic Acid in Renovascular Disease

“…48 Moreover, impairment of 11,12-EET synthesis in mice produced by disruption of the gene-controlling EET synthase caused salt-sensitive hypertension. 49 …”