Effects of epoxyicosatrienoic acids on ion transport in the rabbit cortical collecting tubule

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

“…However, the strong pressure lowering effects of amiloride on Cyp2c44 KO mice fed HS diets corroborates the role played by ENaC in their salt-sensitive phenotype. Taken together, these results identify roles for: (a) ENaC dysfunction as a major component of the hypertensive phenotype of KO mice and (b) the Cyp2c44 epoxygenase and the EETs in the in vivo regulation of ENaC gating and distal sodium excretion (39). Of note, although the pressure differentials between salt-loaded WT and KO mice were similar (35-40 mm Hg) whether measured by ambulatory catheters (Fig.…”

“…The CD participates in the fine tuning of plasma sodium levels, and sodium reabsorption by ENaC is a rate-limiting step in this important function (3, 7). The report that luminal EETs inhibited sodium reabsorption in perfused rabbit CDs was the first indication of roles for these lipids in distal sodium transport (39). Subsequently, the demonstration that: (a) the kidney expression of rat CYP2C23 and mouse Cyp2c44 epoxygenases was salt-sensitive (21,26,33), (b) epoxygenase inhibition caused salt-sensitive hypertension (21,33), and (c) hypertensive Dahl salt-sensitive rats show reduced kidney epoxygenase activity (21,33) suggested antihypertensive roles for these enzymes and their metabolites (21).…”

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

“…On the other hand, the PPARα ligand effectively normalized the blood pressure of hypertensive Cyp4a10 -/-mice ( Figure 4B) and raised their urine epoxygenase metabolites and kidney Cyp2c44 mRNAs to levels similar to or higher than those present in wildtype mice (Table 2) (Figure 4, A and C). This association between an increase in renal Cyp2c44 expression and activity and a reduction in systemic blood pressure supports the antihypertensive functions proposed for the EETs (8-11) and points to the EETs and the AA epoxygenase as endogenous regulators of ENaC activity (20,21). The mechanism(s) by which the Wy regulates renal Cyp2c44 epoxygenase expression …”

“…Thus, for example, earlier studies demonstrated that renal EET biosynthesis was sensitive to dietary salt intake (18), that inhibition of renal epoxygenase caused salt sensitive hypertension (19), and that hypertensive Dahl saltsen sitive rats showed reductions in kidney epoxygenase activity and urinary EET excretion (19). Moreover, studies with isolated rabbit collecting ducts (CDs) suggested a role for the EETs and the P450 epoxygenases in distal sodium excretion (8,9,20) and pointed to ENaC as their molecular target (21). Amiloride and its analogs pro mote sodium excretion and potassium sparing by selective inhibi tion of ENaC (22).…”

Roles of Renal Cytochrome P450-Dependent Arachidonic Acid Metabolites in Hypertension.

“…However, it causes renal vasoconstriction and reduces glomerular filtration rate by the intrarenal infusion in rats (Takahashi et al 1990). It was shown to inhibit sodium flux and sodium reabsorption in isolated collecting tubules in rabbits (Jacobson et al 1984), and the inhibitory effect of sodium reabsorption by angiotensin II was mediated via the generation of 5, 6 EET in cultured proximal tubule cells ). It also inhibit Na flux by increased Ca influx through dihydropyridine sensitive Ca channels in proximal tubular cells in culture (Douglas et al 1990).…”