title: Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo.
abstract: 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-αhydroxylase.
  
  
  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-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.
  
  
  RESULTS
  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 (>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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, United States; Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Carlos
authors.initials: C
authors.lastname: Roncal-Jimenez
authors.forename: Miguel
authors.initials: M
authors.lastname: Lanaspa
authors.forename: Smits
authors.initials: S
authors.lastname: Gerard
authors.forename: Michel
authors.initials: M
authors.lastname: Chonchol
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Diana
authors.initials: D
authors.lastname: Jalal
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D006801:Humans; D033461:Hyperuricemia / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009749:Nutrition Surveys; D016017:Odds Ratio; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D014527:Uric Acid / Q000378:metabolism* / Q000494:pharmacology; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D010281:Parathyroid Hormone; D014807:Vitamin D; D014527:Uric Acid; D013250:Steroid Hydroxylases; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: 1,25 dihydroxy-vitamin D; 1,25(OH)(2)D; 25 hydroxyvitamin D; 25(OH)D; ATX; BMI; CKD; FBXT; GFR; IQR; MBD; MDRD; Mineral and bone disorder; Mineral and bone disorders; Modification of Diet in Renal Disease; NFκB; NHANES; National Health and Nutrition Examination Survey; PTH; Parathyroid hormone; Uric acid; allantoxanamide; body mass index; chronic kidney disease; febuxostat; glomerular filtration rate; inter-quartile range; nuclear factor κ- B; parathyroid hormone