Effect of sex hormones on renal estrogen and angiotensin type 1 receptors in female and male rats

Abstract

Although the mechanisms are not understood, evidence suggests that 17beta-estradiol (E2) confers protection from cardiovascular and renal complications in many diseases. We have reported that E2 decreases angiotensin type 1 receptors (AT1Rs) in different tissues and hypothesize that E2 exerts tonic inhibition on AT1Rs, reducing effects of ANG II. This study determined the effects of E2 and dihydrotestosterone (DHT) on cortical estrogen receptors (ERs) and glomerular AT1R binding in rats. Animals underwent sham operation, ovariectomy (Ovx) or orchidectomy (Cas) and were treated (Ovx +/- E2; Cas +/- DHT) for 3 wk. Cortical ERalpha protein was 2.5 times greater, and ERbeta was 80% less in females vs. males (P < 0.01). Glomerular AT1R binding was lower in females than males [4,657 +/- 838 vs. 7,457 +/- 467 counts per minute (cpm), P < 0.01]. Ovx reduced ERalpha protein by 50%, whereas E2 increased ERalpha expression after Ovx. The decrease in cortical ERalpha in Ovx rats was associated with a significant increase in AT1R binding (6,908 +/- 609 cpm), and E2 prevented this increase. There was no change in ERalpha or AT1R binding following Cas +/- DHT (25 mg) treatment, although Cas did elevate cortical ERbeta (P < 0.01). Interestingly, the high dose DHT (200 mg) elevated ERalpha 150% above intact levels and profoundly decreased AT1R binding (1,824 +/- 705 cpm, P < 0.001 vs. intact male). This indicates that under normal conditions, glomerular AT1R binding is significantly greater in male than female animals, which may be important in development of cardiovascular and renal disease in males. Furthermore, E2 regulates ERalpha and is inversely associated with glomerular AT1R binding, supporting our hypothesis that E2 tonically suppresses AT1Rs and suggesting a potential mechanism for the protective effects of estrogen.

Estrogens and Progression of Diabetic Kidney Damage

“…Our laboratory confirmed by mRNA and western analysis the expression of ER and ER subtypes [52]. Previous studies found that total kidney and mesangial cell ER expression are regulated by the level of estrogens [14,[67][68][69]]. This appears to be the case for podocyte ER expression.…”

Sex differences in the developmental origins of hypertension and cardiorenal disease

“…Rogers et al (105), studying the role of sex hormones in expression of components of renal renin angiotensin in healthy SpragueDawley rats, have suggested that an estrogen-mediated attenuation of renal AT 1 binding is a potential mechanism by which estrogen exerts protection from vascular and renal disease in females (105). When this inhibition is lifted following ovariectomy in their model, or in diabetes or menopause, the resulting increased ANG II signaling increases both the degree of susceptibility to vascular and renal disease and the rate of existing disease progression (105).…”

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

“…We recently published that greater levels of the vasodilatory peptide ANG (1-7) contribute to sex differences in the hypertensive response to chronic ANG II infusion in spontaneously hypertensive rats (SHR), although it is unknown whether there are additional molecular mechanism(s) contributing to sex differences in the blood pressure response to ANG II. Activation of angiotensin type 1 (AT 1 ) receptors mediate most well-known biological functions of ANG II, including the stimulation of oxidative stress, and female SHR have fewer AT 1 receptors than male SHR (43). However, little is known regarding the relative contribution of ANG II-mediated oxidative stress on blood pressure regulation in male vs. female rats.…”