Abstract

In humans, uric acid is an end-product of purine metabolism. Urate excretion from human kidney is tightly regulated by reabsorption and secretion. At least eleven genes have been identified as human renal urate transporters. However, it remains unclear whether all renal tubular cells express the same set of urate transporters. Here we show that renal tubular cells are divided into three distinct cell populations for urate handling. Analysis of healthy human kidneys at single-cell resolution revealed that not all renal tubular cells expressed the same set of urate transporters. Only 32% of renal tubular cells were related to both reabsorption and secretion, while the remaining renal tubular cells were related to either reabsorption or secretion, at 5% and 63% respectively. These results provide physiological insight into the molecular function of the transporters and renal urate handling on cell-units. Our findings also suggest that three different tubular cell populations cooperate to regulate urate excretion from human kidney. Highlight/Key pointsO_LIWe identified three distinct cell populations within the human renal anatomy that predict putative cellular transport mode, and our findings indicate cellular inhomogeneity with distinct roles such as urate secretion and reabsorption. C_LIO_LIOur model of physiological urate handling demonstrates the excretion dynamics in human kidney in terms of single cell-units. C_LIO_LIOur cellular urate transport analyses suggest the reversibility of some urate transporters even in certain physiological conditions. C_LIO_LIThe physiological function of SLC2A9 is not limited to urate reabsorption; it is also involved in urate secretion restriction. C_LIO_LIThis methodology can be applied to investigations of transport mechanisms in general, regardless of epithelial cell types, species, and substrates. C_LI