The Protective Roles of Estrogen Receptor <i>β</i> in Renal Calcium Oxalate Crystal Formation <i>via</i> Reducing the Liver Oxalate Biosynthesis and Renal Oxidative Stress-Mediated Cell Injury

Abstract

Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ER<i>β</i>) signals could suppress hepatic oxalate biosynthesis <i>via</i> transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple <i>in vitro</i> renal cell lines also found that ER<i>β</i> could function <i>via</i> suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ER<i>β</i> suppressed oxalate-induced oxidative stress <i>via</i> transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5' promoter. We further applied two <i>in vivo</i> mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ER<i>β</i> (ER<i>β</i>KO) as well as mice or rats treated with ER<i>β</i> antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ER<i>β</i>-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the <i>in vivo</i> mouse model. Together, results from multiple <i>in vitro</i> cell lines and <i>in vivo</i> mouse/rat models all demonstrate that ER<i>β</i> may protect against renal CaOx crystal deposition <i>via</i> inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.