Role for ovarian hormones in purinoceptor-dependent natriuresis.

BACKGROUND

Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na transport. Activation of these receptors inhibits epithelial Na channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y and P2Y receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y and P2Y) receptors regulating Na excretion compared to male and OVX rats.

METHODS

To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y and P2Y receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E, 0, 10, 100, and 1000 nM) to test whether E increases mRNA expression of P2Y and P2Y receptors.

RESULTS

Acute P2 inhibition attenuated urinary Na excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y and P2Y mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E dose-dependently upregulated P2Y and P2Y mRNA expression in mIMCD3.

CONCLUSION

These data suggest that ovary-intact females have enhanced P2Y and P2Y-dependent regulation of Na handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na handling in premenopausal females.