Loss of the androgen receptor suppresses intrarenal calcium oxalate crystals deposition via altering macrophage recruitment/M2 polarization with change of the miR-185-5p/CSF-1 signals

Abstract

Crystals can trigger a wide range of kidney injuries that may link to the development of kidney stones. Infiltrating macrophages may influence hyperoxaluria-induced intrarenal calcium oxalate (CaOx) crystals deposition, yet their linkage to sex hormones remains unclear. Here we demonstrated that suppressing the androgen receptor (AR) expression in renal tubular epithelial cells increased the macrophage recruitment/M2 polarization that may result in enhancing the phagocytosis of intrarenal CaOx crystals. Mechanism dissection suggested that AR can suppress macrophage colony-stimulating factor 1 (CSF-1) expression via increasing miRNA-185-5p expression to suppress the M2 macrophage polarization-mediated intrarenal CaOx crystals phagocytosis. The preclinical study using glyoxylate-induced intrarenal CaOx crystals deposition mouse model revealed that renal tubule-specific AR knockout mice have less intrarenal CaOx crystals deposition with more recruited M2 macrophages in the kidney compared with the wild-type mice. Results from the in vivo rat model using hydroxy-l-proline-induced CaOx crystals deposition also demonstrated that targeting the AR with ASC-J9® suppressed the intrarenal CaOx crystals deposition via increasing the renal macrophage recruitment/M2 polarization. Together, results from multiple preclinical studies using multiple in vitro cell lines and in vivo mouse/rat models all demonstrated that targeting the AR with a small molecule ASC-J9® may function via altering macrophage recruitment/M2 polarization to decrease the intrarenal CaOx crystals deposition, a key phenotype seen in many kidney stone disease patients with hyperoxaluria.