Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo

ObjectivePatients with gout have lower calcitriol levels that improve when uric acid is lowered. The mechanism of these observations is unknown. We hypothesized that uric acid inhibits 1-αhydroxylase.Materials and methodsIn vivo, Sprague Dawley rats were randomized to control (n = 5), allantoxanamide (n = 8), febuxostat (n = 5), or allantoxanamide + febuxostat (n = 7). Vitamin D, PTH, and 1-αhydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-αhydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor κ-B (NFκB) was inhibited pharmacologically. Finally, to evaluate the potential implications of these findings in humans, the association between uric acid and PTH in humans was evaluated in a cross-sectional analysis of data from the NHANES (2003–2006); n = 9773.Results1,25(OH)2D and 1-αhydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-αhydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NFκB inhibition. In humans, for every 1 mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (> 65 pg/mL) was 1.21 (95% C.I. 1.14, 1.28; P < 0.0001), 1.15 (95% C.I. 1.08, 1.22; P < 0.0001), and 1.16 (95% C.I. 1.03, 1.31; P = 0.02) for all subjects, subjects with estimated GFR ≥ 60, and subjects with estimated GFR < 60 mL/min/1.73 m2 respectively.ConclusionHyperuricemia suppresses 1-αhydroxylase leading to lower 1,25(OH)2D and higher PTH in rats. Our results suggest this is mediated by NFκB. The association between uric acid and PTH in NHANES suggests potential implications for human disease.