The Roles of Intrarenal 20-Hydroxyeicosatetraenoic and Epoxyeicosatrienoic Acids in the Regulation of Renal Function in Hypertensive Ren-2 Transgenic Rats

Abstract

Background: The present study was performed in hypertensive Ren-2 transgenic rats (TGR) and in normotensive Hannover Sprague-Dawley (HanSD) rats. First, the intrarenal protein expression of CYP4A, the enzyme catalyzing the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), and of CYP2C23, the enzyme responsible for epoxyeicosatrienoic acid (EET) production, was evaluated. Second, the renal functional responses to inhibition of the intrarenal formation of 20-HETE and EETs were investigated. Methods: Renal hemodynamics and electrolyte excretion were evaluated in response to the administration of inhibitors of 20-HETE and EET formation into the renal artery. In renal cortical tissue, CYP4A and CYP2C23 protein expression was assessed by Western blot analysis. Urinary concentrations of 20-HETE and EETs were measured using a fluorescent HPLC assay. Results: TGR have higher kidney CYP4A protein expression and urinary 20-HETE excretion but significantly lower CYP2C23 protein expression and urinary EET excretion than HanSD. Intrarenal inhibition of 20-HETE and EET formation decreased sodium excretion in HanSD, whereas inhibition of 20-HETE increased urinary excretion of sodium in TGR without altering renal hemodynamics. Conclusions: Our data suggest that in TGR, deficient intrarenal synthesis of EETs combined with increased synthesis of 20-HETE with its stimulation of tubular sodium absorption may contribute to the development of hypertension in TGR.

Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertensioninduced end-organ damage in Ren-2 transgenic rats

“…Notwithstanding this conclusion, the important role of CYP-derived eicosanoids in the regulation of renal function and blood pressure as well as in the pathophysiology of hypertension and the associated hypertension-induced end-organ damage has been recently documented for ANG II-dependent forms of hypertension [6-11,16,30-32]. Moreover, disturbed intrarenal production and diminished action of 20-HETE combined with intrarenal deficiency of EETs (a consequence of increased sEH-mediated conversion to biologically inactive DHETEs) have been implicated in the pathophysiology of hypertension in transgenic Ren-2 rats (TGR) [11,13]. Evaluation of the proposed in vivo functional role of 20-HETE and EETs is difficult.…”

“…The notion that intrarenal 20-HETE exerts also an antihypertensive action is strengthened by the demonstration that chronic blockade of 20-HETE formation promotes the development of salt-sensitive hypertension in otherwise salt-resistant rats [41]. In a clear contrast with the transport inhibitory effect of 20-HETE observed in normotensive rats and in a number of experimental or genetic hypertensive rat models, in a recent study we found that in hypertensive TGR increased intrarenal 20-HETE concentrations cause sodium retention without decreasing renal haemodynamics, which suggests an increase in the tubular sodium transport [13]. Thus, in hypertensive Ren-2 transgenic rats 20-HETE could be pro-hypertensive both owing to its vasoconstrictor and to the sodium retaining activity.…”

“…As tested in our preliminary experiments, this dose blocks 20-HETE formation selectively and persistently [13]. …”

“…We have found recently that TGR exhibit increased intrarenal levels of 20-HETE and, simultaneously, an intrarenal deficiency of EETs [13]. 20-HETE is a vasoconstrictor and is commonly regarded as a natriuretic agent, a combination of properties forming the background for both its pro- and antihypertensive potential [4,6,7].…”

“…20-HETE is a vasoconstrictor and is commonly regarded as a natriuretic agent, a combination of properties forming the background for both its pro- and antihypertensive potential [4,6,7]. On the other hand, we have recently provided evidence that 20-HETE may induce antinatriuresis in TGR [13]. EETs exhibit anti-hypertensive properties related to their vasodilator and natriuretic potency [4-6].…”