DIFFERENT STRATEGIES EMPLOYED BY CORTEX AND MEDULLA MACROPHAGES TO PREVENT KIDENY STONE FORMATION

Emerging evidence showed that resident macrophages played important roles beyond immunity to fulfill tissue-specific needs. In the kidney, both cortex and medulla are distributed with resident macrophages, but the physiological functions of them in steady state are not well explored. In particular, as tubule obstruction by particles such as mineral stones is a continuous challenge to the kidney, the roles of macrophages in kidney stone development are not fully addressed.

Adult C57BL/6 mice were used in this study. Inducible genetic mice were used to label or deplete kidney macrophages or to deprive macrophages of Slc34a1 expression. High-resolution confocal microscopy were used to reveal the morphology of macrophages and their interactions with kidney tubules. Two-photon microscopy was employed to live record the movements of macrophages in the kidney. Mice were challenged with sodium oxalate to evaluate the functions of macrophages in kidney stone formation.

Most of resident macrophages in the kidney were in close contact with tubules and they formed transtubular protrusions exposed to the urine. The macrophages in the medulla constitutively “sampled” urine contents. They efficiently sequestered and phagocytosed intratubular particles. They could even transmigrate to the tubule lumen to escort the excretion of sedimentary particles. Depleting them or blocking the formation of their transtubular protrusions would expedite kidney stone formation. In contrast, the juxtatubular macrophages in the cortex were not active in movement, but they highly expressed phosphate transporter SLC34A1. They routinely reabsorb phosphate from the urine via SLC34A1. As such, Slc34a1 deprivation from cortex macrophages not only led to phosphaturia, but resulted in a rampant deposition of intratubular calcium phosphate (CaPi) microcrystals, which when in a challenge of oxalate over-exposure, accelerated the formation of kidney stones. Physiologically, cortex macrophages would upregulate SLC34A1 expression upon encountering CaPi microcrystals, which could enhance their ability in phosphate reabsorption as a preventive strategy against mineral stone formation in the downstream renal tubules.

In the kidney, the cortex macrophages preventively limit kidney stone formation by reabsorbing phosphate, and the medulla macrophages remove pre-formed sedimentary particles from the urine. They cooperate in maintaining kidney tubule unobstructed, executing a routine “plumber” role for the renal tubule system.