Progressive renal dysfunction and macrophage infiltration in interstitial fibrosis in an adenine-induced tubulointerstitial nephritis mouse model |
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Authors: | Mizuho Tamura Reiko Aizawa Masatoshi Hori Hiroshi Ozaki |
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Institution: | (1) Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan;(2) Teijin Institute for Bio-medical Research, Teijin Pharma Limited, Hino, Tokyo 191-8512, Japan |
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Abstract: | Adenine phosphoribosyltransferase deficiency in mice or an excessive oral intake of adenine leads to the accumulation of 2,8-dihydroxyadenine
(DHA) in renal tubules and that causes progressive renal dysfunction accompanied by interstitial fibrosis. However, the precise
mechanism responsible for DHA-induced progressive fibrosis is not fully understood. The present study investigates the possible
involvement of monocytes/macrophages in the progressive fibrosis induced by feeding adenine to mice. Urinary calculi were
deposited in tubules on day 7 after the initiation of adenine feeding. Elevation of the serum creatinine level and loss of
body weight were observed in a time-dependent manner, suggesting the development of typical renal dysfunction induced by the
adenine feeding. In renal tissue, mRNA expression of MCP-1, MIP-1α, RANTES, IL-1β, CCR2, TGF-β, α-smooth muscle actin (α-SMA)
and collagen 1a1 was increased in parallel. Along with the increased expression of these genes, a remarkable infiltration
of macrophages into the tubulointerstitial area was observed in a time-dependent manner. In addition, in the tubulointerstitial
area, α-SMA positive fibroblasts were increased in parallel with collagen deposition. These results suggest that the excessive
consumption of adenine leads to progressive renal dysfunction in mice. We speculate that the accumulation of DHA in tubules
might stimulate epithelium to produce MCP-1 and that profibrogenic TGF-β produced by infiltrated macrophages might stimulate
interstitial fibroblasts to produce collagen. These results indicate that macrophage infiltration is one of the triggers that
initiates interstitial fibroblast activation and collagen deposition followed by renal dysfunction. |
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Keywords: | Adenine Tubulointerstitial nephritis Macrophage Interstitial fibrosis Fibroblast |
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