Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo

• Published in: Metabolism, clinical and experimental Vol. 63; no. 1; pp. 150 - 160
• Main Authors: Chen, Wei, Roncal-Jimenez, Carlos, Lanaspa, Miguel, Gerard, Smits, Chonchol, Michel, Johnson, Richard J., Jalal, Diana
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.01.2014; Elsevier
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism; Animals; Biological and medical sciences; Cross-Sectional Studies; Dose-Response Relationship, Drug; Endocrinology & Metabolism; Feeding. Feeding behavior; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Humans; Hyperuricemia - metabolism; Immunoblotting; In Vitro Techniques; Mineral and bone disorders; NF-kappa B p50 Subunit - metabolism; Nutrition Surveys; Odds Ratio; Parathyroid hormone; Parathyroid Hormone - antagonists & inhibitors; Parathyroid Hormone - blood; Random Allocation; Rats; Rats, Sprague-Dawley; Steroid Hydroxylases - antagonists & inhibitors; Uric acid; Uric Acid - metabolism; Uric Acid - pharmacology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vitamin D - metabolism; NFκB; PTH; ATX; 1,25(OH)2D; IQR; Uric acid; MDRD; MBD; GFR; Mineral and bone disorders; Parathyroid hormone; 25(OH)D; FBXT; NHANES; CKD; BMI; chronic kidney disease; nuclear factor κ- B; 25 hydroxyvitamin D; allantoxanamide; Mineral and bone disorder; Modification of Diet in Renal Disease; inter-quartile range; febuxostat; parathyroid hormone; glomerular filtration rate; body mass index; 1,25 dihydroxy-vitamin D; National Health and Nutrition Examination Survey; 1,25(OH) 2D; In vivo; Enzyme; Hydroxylase; Oxidoreductases; In vitro; Endocrinology; 1,25(OH)D
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2013.09.018

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-αhydroxylase. 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-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. 1,25(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 1mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (>65pg/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 <60mL/min/1.73m2 respectively. Hyperuricemia 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.