Abstract
Objective : Proteinuria in chronic glomerulonephritis is not only the result of glomerular damage, but also the main cause of tubulointerstitial damage. The unsaturated fatty acid contained in proteinuria generates oxidant stress during the resorptive process in the proximal tubules and is a cause of tubulointerstitial damage. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of fatty acid that is expressed in the proximal tubules of human kidney. Tubulointerstitial damage induced by fatty acid is prevented by L-FABP, which binds to the excessively loaded fatty acid and is then excreted into urine. Furthermore, L-FABP is activated and plays an important protective role in tubular ischemia. The present study investigated whether tubulary protection in glomerulonephritis may prevent the progression of glomerular damage. Since L-FABP is not expressed in rodents, transgenic mice (L-FABPTg were established by introducing the human chromosome gene including the transcript adjustment area only into the proximal tubules. Then these animals were employed for this study.
Materials and Methods : We induced anti-glomerular basement membrane antibody-mediated glomerulonephritis (Anti-GBM GN) in L-FABPTg mice and wild type littermates (WT), and evaluated the kinetics of proteinuria, polymorphonuclear (PMN) influx, urinary L-FABP concentration, a marker whose lack indicates fibrosis (α-SMA), oxidative stress (HNE) and tubular ischemia (KIM-1), and glomerular histology. In addition, we also orally administered angiotensin II type 1 receptor blocker (ARB : Olmesartan, 6mg/kg body wt/ day) in L-FABPTg mice with Anti-GBM GN.
Results : Glomerular injury and proteinuria before day 3 were significantly prevented in L-FABPTg mice showing a lack of PMN influx at 3 and 6 hours. Proteinuria in L-FABPTg mice gradually increased after day 3 and reached the level shown in WT mice at day 7. WT mice showed glomerular damage with severe endothelial injury, while L-FABPTg differently showed mesangial proliferative glomerulonephritis. Despite the same degree of proteinuria at day 7, tubular expressions of a-SMA, HNE and KIM-1 were clearly decreased. Proteinuria and glomerular damage in L-FABPTg mice were significantly inhibited by ARB. Conclusions : These present findings suggest that the enhancement of tubular L-FABP expression may prevent not only tubulointerstitial damage but also the progression of glomerular damage.
