Estrogen Downregulates NaPi‐IIa in the Kidney Through the Activation of Both Estrogen Receptors ER alpha and ER beta

Abstract

In these studies, we examined the effect of estrogen (EST) on phosphate transporters in the kidney and determined the respective role of estrogen receptors (ER) isoforms (ERα and ERβ) in this effect. We first demonstrated by RT‐PCR that both ERα and ERβ are expressed in the proximal tubule (PT) cells. Next, OVX rats were injected with EST or its vehicle for 3 days and the expression of Pi transporters in the PT was examined in the kidney cortex. Molecular studies demonstrated that NaPi‐IIa mRNA and protein were significantly reduced by EST in a dose‐dependent manner, whereas the expression levels of NaPi‐IIc and Pit2 were unchanged. Using specific agonists of either ERα (4,4′,4″‐(4‐ Propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol or PPT) or ERβ (2,3‐ bis(4‐Hydroxyphenyl)‐propionitrile or DPN) or both (PPT+DPN), we demonstrated that food intake was decreased in PPT‐ and PPT+DPN− but not in DPN‐treated rats. PPT and DPN alone did not affect NaPi‐IIa protein abundance and did not cause phosphaturia despite a decrease in the expression of its mRNA levels. However, PPT+DPN caused a sharp downregulation of NaPi‐IIa along with significant urinary Pi wasting. These studies demonstrate that the phosphaturic effect of EST is mediated specifically through downregulation of NaPi‐IIa and that this effect is mediated via a complex mechanism involving the activation of both ERα and ERβ isoforms. NIH/NIDDK 5RO1DK83582