GPER1 activation regulates renal purinergic P2Y ₂ receptor natriuretic pathway

Estradiol activates the G protein-coupled estrogen receptor 1 (GPER1), which promotes natriuresis in female rats. Extracellular adenosine triphosphate (ATP) released via connexin 30 (Cx30) hemichannels activates purinergic P2Y₂ receptor, promoting Na⁺ excretion via inhibiting epithelial Na⁺ channel (ENaC) activity. Interestingly, ovariectomy downregulates renal P2Y₂ receptor expression in Sprague Dawley (SD) rats. We hypothesized that GPER1 activation regulates renal Cx30/ATP/P2Y₂/ENaC signaling pathway in females. To test our hypothesis, female SD rats were implanted with telemetry transmitters and then ovariectomized (OVX) and simultaneously implanted with osmotic minipumps to deliver either the selective GPER1 agonist G1 or vehicle for 3 wk. Rats were fed a normal-salt (0.4% NaCl) diet from the start of the experimental protocol until <i>day 14</i> after ovariectomy. Afterward, rats were shifted to a high-salt diet (4% NaCl) for 7 days. Ovariectomy increased blood pressure during normal salt intake. High salt intake elicited further increases in mean arterial pressure. These increases in blood pressure were prevented by G1. Cx30 and P2Y₂ receptor mRNA expressions were higher in the cortex of OVX SD rats with G1 treatment plus high salt intake. Genetic deletion of GPER1 in mice reduced the renal expression of Cx30 and P2Y₂ receptor. Importantly, renal medullary infusion of G1 in ovary-intact female rats increased urinary ATP and Na⁺ excretion. Furthermore, P2 receptor blockade by suramin blocked GPER1-evoked natriuresis. These findings indicate that GPER1 upregulates the natriuretic Cx30/ATP/P2Y₂ receptor signaling pathway in the kidney, which may contribute to the blood pressure-lowering response to GPER1 activation.<b>NEW & NOTEWORTHY</b> Systemic GPER1 activation upregulated renal Cx30 and P2Y₂ receptor mRNA expression in ovariectomized rats, whereas genetic deletion of GPER1 downregulated renal Cx30 and P2Y₂ receptor mRNA expression in ovary-intact female mice. Acute renal medullary GPER1 activation enhances natriuresis and urinary ATP excretion in ovary-intact female rats. These findings indicate that GPER1 regulates the natriuretic Cx30/ATP/P2Y₂ receptor signaling pathway in the kidney, which may contribute to the blood pressure-lowering response to GPER1 activation.