An evaluation of the development of experimental membranous nephropathy

Abstract

Heymann nephritis is a rat model of glomerulonephritis with morphologic manifestations of human membranous nephropathy. This model is generated by immunizing rats with Fx1A antigen. Passive Heymann's nephritis (PHN) can be produced by the administration of anti-Fx1A antibody (anti-Fx1A Ab) (with abnormal proteinuria appearing in 5 days). Studies were designed to examine the evolution of temporal changes in protein excretion, the glomerular ultrafiltration coefficient (LpA) and morphology of glomerular capillary three and five days after induction of PHN. Glomerular hemodynamic evaluation by micropuncture in euvolemic rats with PHN revealed normal values for nephron filtration rate (SNGFR), LpA and the glomerular hydrostatic pressure gradient (delta P) at day three, but by day five the whole kidney GFR and SNGFR were decreased, delta P increased and LpA significantly reduced. Glomerular binding of anti-Fx1A Ab increased from 38 micrograms/7.6 X 10(4) glomeruli on day three to 52 micrograms on day five. Immune complex deposits evaluated by immunofluorescence and electron microscopy appeared larger and were better defined on day five than on day three. Epithelial foot process fusion was more extensive on day five than day three. The onset of increased proteinuria correlated temporally with a reduction in LpA on day five, which in turn correlated with increased antibody binding, immune deposit accumulation and fusion of epithelial cell foot processes.

Sodium Sensitivity of Blood Pressure Appearing Before Hypertension and Related to Histological Damage in Immunoglobulin A Nephropathy

“…In rats with experimental nephritis or 1-sided nephrectomy, glomerular hypertension appears without hypertension. 21,22,25,26 The glomerular pressure in our patients with normal to high-normal pressure may be higher than that in our patients with optimal pressure. We calculated the glomerular pressure in the patients of this study by the method used in our previous study.…”

“…SSI was different among the groups. The median glomerulosclerosis score was different in the groups (optimal group, 33 [25th to 75th percentile, 3, 82]; normal to high-normal group, 125 [25,185]; and hypertensive group, 160 [106, 176] Figure 2a). The median score for tubulointerstitial damage was different among the groups (optimal group, 5 [0, 9]; normal to high-normal group, 10 [10,30]; and hypertensive group, 30 [20,40]; Figure 2b).…”

IL-4 Therapy Prevents the Development of Proteinuria in Active Heymann Nephritis by Inhibition of Tc1 Cells

“…The presence of subepithelial IgG and C3 in the GBM is one of the hallmarks of HN and human membranous nephropathy, and the importance of the early complement components in PHN is well established. Rats depleted of complement with cobra venom factor do not develop proteinuria in PHN (13,46,47), and Baker et al (48) showed that depletion of C6 with a mAb prevented proteinuria in PHN. However, the pathogenic role of the MAC complex has been questioned with the induction of both active HN (15) and PHN (49,50) in a C6-deficient PVG rat strain.…”

“…Activation of C3 by anti-Fx1A Abs leads to formation of the membrane attack complex (C5b-9/MAC), which is thought to mediate sublytic injury to GEC, synthesis of abnormal glomerular basement membrane (GBM) matrix, and proteinuria (10,11). In passive HN (PHN), C3 depletion with cobra venom factor abrogates proteinuria, suggesting complement is the principal mediator of glomerular injury (12,13). Ab responses that block the function of the complement regulatory molecule Crry, the rodent analogue of human decay-accelerating factor and monocyte chemoattractant protein, are also necessary for the development of proteinuria in HN (14).…”

Studies on Antinephritic Effect of TJ-8014, a New Japanese Herbal Medicine (4): Effects on Accelerated Passive Heymann Nephritis in Rats

“…The formation of the C5b-9 in rat PHN has been shown to stimulate the production of arachidonic acid, prostaglandin F2a (PGF2a) and thromboxne A2 (TXA2) (14). The reduction of the RBF of rats with APHN is probably due to the increase in glomerular synthesis of prostanoids such as PGF2a and TXA2 that induce vasoconstriction (15,16). At the present time, TJ-8014, given as a single p.o.-dose of 4.0 g/kg, inhibited the de crease in the RBF by 57%.…”