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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 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.

Voltage-gated sodium channels (Na(v)) underlie the rapid upstroke of action potentials in excitable tissues. Binding of channel-interactive proteins is essential for controlling fast and long-term inactivation. In the structure of the complex of the carboxy-terminal portion of Na(v)1.5 (CTNa(v)1.5) with calmodulin (CaM)-Mg(2+) reported here, both CaM lobes interact with the CTNa(v)1.5. On the basis of the differences between this structure and that of an inactivated complex, we propose that the structure reported here represents a non-inactivated state of the CTNa(v), that is, the state that is poised for activation. Electrophysiological characterization of mutants further supports the importance of the interactions identified in the structure. Isothermal titration calorimetry experiments show that CaM binds to CTNa(v)1.5 with high affinity. The results of this study provide unique insights into the physiological activation and the pathophysiology of Na(v) channels.