Mariana Urquiaga, Nicholas Sumpter, Megan Leask, Tony Merriman
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham
Background: Gout develops in the setting of hyperuricemia (HU). Urate is produced by xanthine dehydrogenase (XOR), encoded by XDH in humans and Xdh in mice. It is accepted knowledge that urate production occurs mainly in the liver. However, we found that male-specific genetic association of XDH with serum urate level and risk of gout specifically co-localizes with genetic control of prostatic expression of XDH. Supporting that there is XOR activity in the prostate, XOR is active and urate is present in the mouse prostate. These data suggest that the prostate plays a role in the risk of HU and gout in men. Our objective was to determine the cell-specific expression of XDH and key urate transporters genes in the prostates of humans and mice.
Methodology: We conducted a literature search to identify studies that had conducted single-cell RNA sequencing of noncancerous human and mouse prostate tissue. We downloaded their publicly available raw count data and took it through an analysis pipeline. Using the Seurat package in R, we completed quality control, normalization, integration, clustering, and identification of cell clusters based on known markers. Then, we evaluated the level of expression of a list of genes involved in urate metabolism in each cell type. We tested for XDH and the following genes encoding urate transporters: ABCG2, SLC2A9, ABCC4, SLC17A1-4, SLC22A6-8, SLC22A11-13 (and equivalents in mice).
Findings: We found two studies with publicly available human prostate noncancerous single-cell RNA sequencing data (1, 2). Henry et al. sequenced tissue from three young organ donors, and Crowley et al. used tissue from three middle-aged men with benign prostatic hyperplasia. In both human datasets, we found that XDH, SLC2A9 (encodes GLUT9), and ABCC4 (encodes MRP4) have overlapping expression in epithelial cells, and expression of ABCG2 (encodes ABCG2) is restricted to endothelial cells (Figure 1). The other genes tested had negligible expression. We identified one study that sequenced prostate tissue from three 10-week-old mice. Xdh, Abcg2, Slc2a9, and Abcc4 were all expressed in epithelial and stromal cells. Other genes had negligible expression. We did not find a cell cluster that we could identify as endothelial cells based on known cell markers.
Significance: The expression pattern of XDH, SLC2A9, ABCC4, and ABCG2 in human prostate tissue provides a potential mechanism for prostatic production and handling of urate. The mechanism is consistent with a hypothesis of production of urate by XOR in epithelial cells, transport to the glandular lumen through GLUT9 and MRP4, and transport into the blood by ABCG2. Our findings suggest that the prostate plays a previously unrecognized role in urate homeostasis and the risk of gout in men.
References: 1. Henry GH, Malewska A, Joseph DB, Malladi VS, Lee J, Torrealba J, et al. A Cellular Anatomy of the Normal Adult Human Prostate and Prostatic Urethra. Cell Rep. 2018;25(12):3530-42.e5. 2. Crowley L, Cambuli F, Aparicio L, Shibata M, Robinson BD, Xuan S, et al. A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors. Elife. 2020;9