title: A novel model of adenine-induced tubulointerstitial nephropathy in mice.
abstract: BACKGROUND
  In vivo models of uremia are important tools to study numerous aspects of acute and chronic kidney disease. Mouse models are pivotal because most genetically engineered animal models are mice, which allow dissecting the impact of selected target genes in renal failure. Adenine-based protocols to induce renal failure are available in rats, but have not been adapted in mice due to their reluctance to consume adenine. In the current paper we developed a novel method for induction of renal failure through dietary delivery of adenine mixed in a casein-based diet.
  
  
  RESULTS
  After an induction phase, a stable model of renal impairment was obtained (target urea range 80-100 mg/dL), mimicking several aspects of chronic kidney disease - mineral and bone disorder including secondary hyperparathyroidism, bone abnormalities and pathological elevation of FGF23. No deaths occurred and the level of uremia was adaptable through adjustments of the adenine content, providing significant advantages compared to existing models. In an 8-week proof-of-concept study, renal histology showed mainly a tubulointerstitial damage with infiltrating leukocytes, interstitial edema and widening of the Bownman's space. Fibrosis was present in most animals as defined by histology and gene expression changes of fibrosis markers. Parathyroid cell proliferation was markedly increased but without signs of glandular hypertrophy. Skeletal histology showed increased trabecular bone and bone marrow adiposity whereas bone biomarkers (CTX and PINP) suggested higher bone formation, but surprisingly, lower bone resorption and perturbations in mineral metabolism.
  
  
  CONCLUSIONS
  We present a novel, non-surgical method for induction of renal failure in mice. This is an important complement to existing uremic models for pathophysiological studies in acute and chronic kidney disease, especially in terms of tubulointerstitial lesions.
authors.forename: Ting
authors.initials: T
authors.lastname: Jia
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.forename: Karolina
authors.initials: K
authors.lastname: Lindberg
authors.forename: Risul
authors.initials: R
authors.lastname: Amin
authors.forename: Karin
authors.initials: K
authors.lastname: Edvardsson
authors.forename: Bengt
authors.initials: B
authors.lastname: Lindholm
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.forename: Yves
authors.initials: Y
authors.lastname: Sabbagh
authors.forename: Susan
authors.initials: S
authors.lastname: Schiavi
authors.forename: Tobias E
authors.initials: TE
authors.lastname: Larsson
mesh_terms: D000225:Adenine / Q000008:administration & dosage* / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*
chemical_list: C000717428:Fgf23 protein, mouse; D000089703:Fibroblast Growth Factor-23; D000225:Adenine