Effect of indomethacin on glomerular permselectivity and hemodynamics in nephrotoxic serum nephritis

The present study was undertaken to determine the effects of prostaglandin synthesis inhibition on glomerular hemodynamics in nephrotoxic serum nephritis and to elucidate the mechanisms by which prostaglandin synthesis inhibition reduces proteinuria in nephritic rats. Dextran sieving studies were performed before and after intravenous administration of indomethacin to control rats and to nephritic rats with heavy proteinuria. Indomethacin did not significantly alter mean arterial pressure, glomerular filtration rate or proteinuria in control rats nor were significant changes in dextran sieving observed. By contrast, in nephritic rats indomethacin significantly reduced glomerular filtration rate (2.58 ± 0.50 vs. 1.39 ± 0.27 ml/min, P<0.001), proteinuria (0.198 ± 0.079 vs. 0.048 ± 0.019 mg/min, P < 0.05) and filtration rate-corrected proteinuria (0.059 ± 0.033 vs. 0.031 ± 0.013 mg/ml GFR, P < 0.05). The fractional clearance of neutral dextrans with molecular radii exceeding 42 Å were elevated above control values in nephritic rats (P < 0.05). After administration of indomethacin, the fractional clearance of neutral dextrans uniformly declined toward control values and remained elevated only for molecular radii exceeding 54 Å. Assessment of glomerular hemodynamics in nephritic rats before and after indomethacin showed significant declines in single nephron filtration rate (31.5 ± 3.0 vs. 21.2 ± 2.5 nl/min, P < 0.02), glomerular plasma flow rate (99.5 ± 6.7 vs. 68.5 ± 7.8 nl/min, P < 0.05) and glomerular ultrafiltration coefficient (0.0430 ± 0.0033 vs. 0.0339 ± 0.0032 nl·sec^-1·mm Hg^-1, P < 0.05). Indomethacin did not significantly change these parameters in control rats. Utilizing a heteroporous mathematical model of the glomerular basement membrane, we calculated that the proportion of glomerular filtrate permeating the shunt pathway was elevated above control values in nephritis (0.33% vs. 0.17%), but declined to a value of 0.21% after administration of indomethacin. These data suggest that in nephrotoxic serum nephritis prostaglandin inhibition reduces proteinuria by reducing filtration rate and by improving glomerular size-selectivity via decreased utilization of the shunt pathway.