AUTHOR=Wu Shouhai , Li Chuang , Li Yizhen , Liu Junyi , Rong Cuiping , Pei Hongfei , Li Xiong , Zeng Xiang , Mao Wei 

TITLE=SLC2A9 rs16890979 reduces uric acid absorption by kidney organoids

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1268226

DOI=10.3389/fcell.2023.1268226

ISSN=2296-634X

ABSTRACT=<p><bold>Introduction:</bold> The excretion and absorption of uric acid (UA) by the kidneys helps regulate serum UA levels. GLUT9, encoded by <italic>SLC2A9</italic>, is mainly expressed in the renal tubules responsible for UA absorption. <italic>SLC2A9</italic> polymorphisms are associated with different serum UA levels. However, the lack of proper <italic>in vitro</italic> models has stalled research on the mechanisms of single nucleotide polymorphisms (SNPs) that affect UA metabolism in human urate transporters.</p><p><bold>Methods:</bold> In this study, we constructed a gene-edited human embryonic stem cells-9 (ESC-H9) derived kidney organoid bearing rs16890979, an <italic>SLC2A9</italic> missense mutation with undetermined associations with hyperuricemia or hypouricemia. Kidney organoids derived from ESC-H9 with genetical overexpression (OE) and low expression (shRNA) of <italic>SLC2A9</italic> to serve as controls to study the function of <italic>SLC2A9</italic>. The function of rs16890979 on UA metabolism was evaluated after placing the organoids to urate-containing medium and following histopathological analysis.</p><p><bold>Results:</bold> The kidney organoids with heterozygous or homozygous rs16890979 mutations showed normal <italic>SLC2A9</italic> expression levels and histological distribution, phenotypically similar to the wild-type controls. However, reduced absorption of UA by the kidney organoids with rs16890979 mutants was observed. This finding together with the observation that UA absorption is increased in organoids with <italic>SLC2A9</italic> overexpression and decreased in those with <italic>SLC2A9</italic> knockdown, suggest that GLUT9 is responsible for UA absorption, and the rs16890979 SNP may compromise this functionality. Moreover, epithelial-mesenchymal transition (EMT) was detected in organoids after UA treatment, especially in the kidney organoid carrying GLUT9<sup>OE</sup>, suggesting the cytobiological mechanism explaining the pathological features in hyperuricosuria-related renal injury.</p><p><bold>Discussion:</bold> This study showing the transitional value of kidney organoid modeling the function of SNPs on UA metabolism. With a defined genetic background and a confirmed UA absorption function should be useful for studies on renal histological, cellular, and molecular mechanisms with this organoid model.</p>