Urinary excretion of human liver-type fatty acid-binding protein (hL-FABP

No abstract

It is the FFAs bound to albumin, rather than albumin itself, which cause severe tubulointerstitial damage by being reabsorbed into the proximal tubule. To our knowledge, this is the first in vivo observation in which FFAs have caused severe tubulointerstitial injury.

Several lines of evidence show the importance of angiotensin II (AII) in renal injuries, especially when hemodynamic abnormalities are involved. To elucidate the role of AII in immune-mediated renal injury, we studied anti-glomerular basement membrane (GBM) nephritis in AII type 1a receptor (AT1a)-deficient homozygous (AT1a -/-) and wild-type (AT1a +/+ ) mice. A transient activation of the renin-angiotensin system (RAS) was observed in both groups of mice at around day 1. A renal expression of monocyte chemoattractant protein-1 (MCP-1) was transiently induced at six hours in both groups, which was then downregulated at day 1. In the AT1a +/+ mice, after RAS activation, the glomerular expression of MCP-1 was exacerbated at days 7 and 14. Thereafter, severe proteinuria developed, and the renal expressions of transforming growth factor-β1 (TGF-β1) and collagen type I increased, resulting in severe glomerulosclerosis and interstitial fibrosis. In contrast, glomerular expression of MCP-1, proteinuria, and tissue damage were markedly ameliorated in the AT1a -/-mice. Because this amelioration is likely due to the lack of AT1a, we can conclude that AII action, mediated by AT1a, plays a pathogenic role in anti-GBM nephritis, in which AII may contribute to the exacerbation of glomerular MCP-1 expression. These results suggest the involvement of AII in immune-mediated renal injuries. J. Clin. Invest. 103:627-635 (1999) MethodsAnimals. To obtain AT1a-deficient heterozygous (AT1a +/-) mice that have C57Bl/6 background, a germline chimera derived from TT2 embryonic stem (ES) cells with a targeted mutation of the AT1a gene as described previously (16), was backcrossed for five generations with C57Bl/6 mice. The resulting AT1a +/-F 5 mice were then intercrossed to generate the homozygous (AT1a -/-) mice. Concerning the genotype of the renin gene (17) in the AT1a -/-mice, Southern blot analysis was performed as described previously (18), and identity of the Ren-1C gene with that of C57Bl/6 mice was confirmed (Fig. 1). The AT1a -/-mice were then inbred to prepare the enough number of animals for the present study. As AT1a +/+ mice, C57Bl/6 mice were purchased from Japan Clea Co. (Tokyo, Japan). Only male mice at the age of 10 weeks were used for the studies. For the isolation of GBM and the preparation of anti-GBM antiserum (AS), ddy mice and Japanese white rabbits, respectively, were purchased from local breeders.Preparation of rabbit anti-GBM AS. The preparation of anti-GBM AS was performed as described by Nagai et al. (19). In brief, glomeruli were isolated by differential sieving from the mouse renal cortex and disrupted by sonication. The GBM was collected by centrifugation and emulsified with CFA (Difco Laboratories, Detroit, Michigan, USA). Anti-GBM AS was raised in Japanese white rabbits by repeated immunization with mouse GBM.Induction of anti-GBM nephritis. Anti-GBM nephritis was induced in the AT1a -/-and AT1a +/+ mice according to the method described by Nagai et al. (19). In brief, mice were immunized intraperitoneal...

No abstract