The AR/miR-185-5p/TGF-β axis in renal tubular epithelial cells may regulate hyperuricemia-induced renal crystal deposition by impairing macrophage recruitment and M2 polarization

This study investigated whether androgen receptor (AR) signaling in renal tubular epithelial cells contributes to altered macrophage responses and renal crystal deposition under hyperuricemic conditions. We integrated clinical correlation analyses, in vitro genetic manipulations in HK-2 cells and THP-1 macrophage co-cultures, and an in vivo rat model of hyperuricemia-induced crystalluria. Uric acid exposure increased AR and miR-185-5p expression in HK-2 cells. In co-culture experiments, elevated miR-185-5p suppressed TGF-β secretion, altered macrophage migration, increased M1-associated markers, and decreased M2-associated markers. In vivo, targeted inhibition of AR or miR-185-5p significantly restored renal TGF-β levels, increased M2-associated marker expression, attenuated tubular injury, and markedly reduced crystal deposition compared to untreated hyperuricemic controls. Furthermore, pharmacological blockade using enzalutamide mirrored these protective effects. In conclusion, we identify a novel pathogenic cascade where uric acid-driven AR signaling disrupts the renal immune microenvironment through miR-185-5p-mediated TGF-β suppression, ultimately driving renal crystal deposition.