Progressive renal dysfunction and macrophage infiltration in interstitial fibrosis in an adenine-induced...

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-1alpha, RANTES, IL-1beta, CCR2, TGF-beta, alpha-smooth muscle actin (alpha-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, alpha-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-beta 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.