Kidney cortex macrophages prevent the formation of mineral stones by reabsorbing phosphate from the urine

Abstract

Resident macrophages are important in maintaining tissue homeostasis by meeting specialized physiological demands and mitigating the unique stresses each tissue endures. In the kidney, urine is formed in a process of glomerular filtration and tubular reabsorption. Supersaturation of mineral solutes such as calcium phosphate poses a persistent challenge to the kidney; if left unchecked, kidneys stones form, which will cause tubular obstruction and even kidney failure. However, cellular mechanisms of preventing kidney stone formation remain incompletely understood. In this study, we found that resident macrophages in kidney cortex distinguishably expressed phosphate transporter SLC34A1. These cells extend transtubular protrusions and were capable of reabsorbing phosphate from the urine through the SLC34A1, a function previously only attributed to tubular epithelial cells. Depletion of Slc34a1 from kidney cortex macrophages led to increased urinary phosphate excretion, disrupting body phosphorus balance. More importantly, loss of macrophage-mediated phosphate reabsorption from the urine resulted in a drastic over-deposition of calcium phosphate microcrystals in kidney tubules, particularly in the late proximal tubules of inner cortex where intratubular calcium concentration is high. This also accelerated mineral stone formation. Exposure to mineral crystals stimulated cortex macrophages to upregulate SLC34A1 expression, a response mechanistically driven by lysosomal disruption. As such, cortex macrophages employed phosphate reabsorption as a proactive strategy to prevent mineral stone formation.