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

Wei Zhu,Chawnshang Chang,David Bushinsky,Fuju Chou,Tongzu Liu,Shuyuan Yeh,Li Zuo,Guohua Zeng,Zhijian Zhao

doi:10.1038/s41419-019-1358-y

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.

Highlights

Kidney stone disease is a common urological disease that poses a significant health care burden[1]
Targeting androgen receptor (AR) in renal tubular epithelial cells increased the recruitment of macrophages As recent studies indicate that macrophages may alter the intrarenal calcium oxalate (CaOx) crystals elimination[14], we were interested in testing the impact of the AR on the recruitment of macrophages to renal epithelial cells
The results revealed that knocking down AR increased the HK-2 cells conditioned media (CM) capacity to better recruit the M0-MΦs using the transwell migration system (Fig. 1b)

Summary

Introduction

Kidney stone disease is a common urological disease that poses a significant health care burden[1]. Several in vitro[4,5,6] and in vivo[7] studies indicated that the CaOx crystals deposition and subsequent elimination could be altered by infiltrating macrophages, which are functionally classified into two types, pro-inflammatory M1 and anti-inflammatory M2 macrophages. Males have a higher kidney stone incidence compared with females, indicating that sex hormones may function through their receptors to influence kidney stone disease[9,10,11]. Studies indicated that the expression of the androgen receptor (AR) was higher in male patients with kidney stone disease[12,13], and Liang et al.[12] found AR signaling could promote CaOx crystals deposition via increasing liver oxalate biosynthesis and renal oxidative stress. The impact of AR signaling through altering the infiltrating macrophages to influence the intrarenal CaOx crystals deposition and elimination, remains unclear

Methods

Results

Conclusion