Short-term oral gavage administration of adenine induces a model of fibrotic kidney disease in rats

The adenine model of kidney disease typically involves dietary delivery of adenine over several weeks. This model can be variable in its disease progression and can result in significant mortality. In the current study, the amount of adenine delivered to rats was controlled by utilizing oral gavage...

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Published in:	Journal of pharmacological and toxicological methods Vol. 94; no. Pt 1; pp. 34 - 43
Main Authors:	Zhu, Chang Z., Doyle, Kelly J., Nikkel, Arthur L., Olsen, Lauren, Namovic, Marian T., Salte, Katherine, Widomski, Deborah, Su, Zhi, Donnelly-Roberts, Diana L., Gopalakrishnan, Murali M., McGaraughty, Steve
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2018
Subjects:	Acute kidney injury Adenine Adenine - administration & dosage Administration, Oral Animals Biomarkers - urine Fibrosis - chemically induced Fibrosis - metabolism Fibrosis - urine Glomerular Filtration Rate - drug effects Inflammation - chemically induced Inflammation - metabolism Inflammation - urine Kidney - drug effects Kidney - metabolism Kidney Diseases - chemically induced Kidney Diseases - metabolism Kidney Diseases - urine Male Rats Rats, Sprague-Dawley RNA, Messenger - metabolism Tubulointerstitial fibrosis Urinary biomarkers Adenine Tubulointerstitial fibrosis Urinary biomarkers Acute kidney injury
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Summary:	The adenine model of kidney disease typically involves dietary delivery of adenine over several weeks. This model can be variable in its disease progression and can result in significant mortality. In the current study, the amount of adenine delivered to rats was controlled by utilizing oral gavage administration over a short period in an attempt to induce robust renal pathology while addressing variability and viability of the animals. Adenine (150 or 200 mg/kg) was administered via oral gavage for 10 consecutive days, and assessed over a total of 20 days. Both adenine dose groups manifested pathophysiological features of kidney disease such as proteinuria, elevated serum creatinine and BUN, and tubulointerstitial fibrosis. The animals also displayed a decline in glomerular filtration rate. Renal mRNA expression of genes associated with injury, inflammation, and fibrosis (i.e., Col1a1, Acta2, Serpine1, Timp1, Fn-Eda, Tgfb1, Ccl2, Nlrp3, Aqp1 and Ccnd1) were elevated as were urinary biomarkers that have translational utility (i.e., clusterin, KIM-1, MCP-1, OPN, NGAL, B2M, calbindin, and cystatin C). All disease endpoints were more pronounced in the 200 mg/kg group, however, while measures of tissue fibrosis were sustained, there was partial recovery by day 20 in functional readouts. No mortality was observed in either dose group. Short-term delivery of adenine via precise gavage delivery induced a robust model with hallmarks of fibrotic kidney disease, had limited variance between animals, and no animal morbidity within the 20 days studied. This model represents a methodical alternative to long-term dietary dosing of adenine.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1056-8719 1873-488X
DOI:	10.1016/j.vascn.2018.04.003