Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo

Objective. Patients 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-alpha hydroxylase. Materials and methods. In 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-ahydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-alpha hydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor kappa-B (NF kappa B) 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. Results. 1,25(OH)(2)D and 1-ahydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-alpha hydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NF kappa B 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 m(2) respectively. Conclusion. Hyperuricemia suppresses 1-alpha hydroxylase leading to lower 1,25(OH)(2)D and higher PTH in rats. Our results suggest this is mediated by NF kappa B. The association between uric acid and PTH in NHANES suggests potential implications for human disease. (C) 2014 Elsevier Inc. All rights reserved.