Renal tubular uric acid influences water reabsorption, urine concentration, and K+ homeostasis
Authors: Zapf Ava , Halperin Kuhns Victoria , Woodward Owen 
Published: May 2023

Loss of uricase ( UOX) in humans resulted in significant increases of circulating uric acid, (mostly urate at physiological pH) with commiserate increases in filtered and tubular urate in the nephron. Together, increased urate concentration and acidic urine pH should promote urate precipitation and stone formation, yet uric acid stones are relatively rare in healthy humans, suggesting specific renal protective mechanisms to combat urate precipitation. In our previous work, we found the introduction of a human hyperuricemia/gout risk mutation into the mouse Abcg2 gene results in a under excretion type of hyperuricemia, with reduced fractional urate excretion (FEUA). These mice also presented with significantly increased urine osmolality, increased Aqp3 gene expression, and an unexplained increase in plasma K+. We hypothesized if reduced tubular urate resulted in increased water reabsorption and urine concentration, then higher levels of tubular urate may reduce water reabsorption and urine concentration as a protective measure against urate precipitation. Here, we used a genetic model of over production hyperuricemia (inducible Uox KO) to better understand the role of tubular urate in regulating water reabsorption and urine concentration. We induced Uox KO and hyperuricemia in adult males at 9 weeks of age. At 2 weeks or 26 weeks post induction, we measured plasma and urine electrolytes and conducted whole kidney RNAseq analysis. As previously reported, 2 weeks after induction the animals had significantly higher FEUA (n=5,7; p<0.03) and urinary urate excretion (n=7; p<0.01). These animals also had significantly decreased urine concentrations (n=12; p<0.05) but no change in plasma osmolality or plasma electrolytes. After 26 weeks of chronic hyperuricemia, male animals presented with decreased urine concentration (n=8-10; p<0.05), increased urinary flow (n=4-5; p<0.05), increased water consumption (ml/24hrs; n=4-10; p<0.05), and increased plasma osmolality (n=6; p<0.05). DEG analysis revealed mRNA of Aqp 2/3/4 were all significantly decreased in the chronic hyperuricemic animals (log2 fold change -0.84/-0.33/-0.87; n=5; p<0.01). Hyperuricemic animals also showed significantly decreased plasma K+ (n=6; p<0.01). Interestingly, pathway analysis of DEG genes revealed enrichment in aldosterone gene sets (DEG genes included: Sgk1, Kcnj1, Scnn1g, and Scnn1b). This prompted us to measure urinary aldosterone levels and found them to be significantly reduced in the hyperuricemic animals (n=4-8; p<0.05). Our findings present a renal mechanism of protection from stone formation that promotes a diuresis and down regulation of aldosterone and Aqp genes, even at the risk of increasing plasma osmolality and disruption of K+ homeostasis. Understanding the relationship between urate handling in the kidney and effects on electrolytes might reveal beneficial adaptations gained in the human lineage when the UOX gene was lost.

NIH/NIDDK R01DK114091

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.