A novel model of adenine-induced tubulointerstitial nephropathy in mice

BMC Nephrology

Tobias E Larsson⁴  Susan Schiavi⁵  Yves Sabbagh⁵  Annika Wernerson¹  Göran Andersson²  Bengt Lindholm³  Karin Edvardsson¹  Risul Amin¹  Karolina Lindberg¹  Hannes Olauson¹  Ting Jia³ 

[1] Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden;Department of Pathology, Karolinska Institutet, Stockholm, Sweden;Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden;Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden;Sanofi-Genzyme R&D Center, Genzyme, A Sanofi Company, Framingham, USA

关键词: Experimental renal failure;    Mineral metabolism;    FGF23;    FGF-23;    CKD-MBD;    Chronic kidney disease;    CKD;   

Others  :  1082923
DOI  :  10.1186/1471-2369-14-116

 received in 2012-08-21, accepted in 2013-05-17,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Jia et al.; licensee BioMed Central Ltd.

【 图 表 】

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