Role for ovarian hormones in purinoceptor-dependent natriuresis

Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y₂ and P2Y₄ 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 P2Y₂ and P2Y₄ 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 (P2Y₂ and P2Y₄) receptors regulating Na⁺ excretion compared to male and OVX rats.

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 P2Y₂ and P2Y₄ 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 (E₂, 0, 10, 100, and 1000 nM) to test whether E₂ increases mRNA expression of P2Y₂ and P2Y₄ receptors.

Acute P2 inhibition attenuated urinary Na⁺ excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y₂ and P2Y₄ 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 P2Y₂ receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E₂ dose-dependently upregulated P2Y₂ and P2Y₄ mRNA expression in mIMCD3.

These data suggest that ovary-intact females have enhanced P2Y₂ and P2Y₄-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.