The specific mechanism whereby superficial nephron glomerular filtration rate (sngfr) is reduced after the administration of benzolamide, a carbonic anhydrase inhibitor with a primary inhibitory effect in the proximal tubule, have been examined by measuring pertinent pressures, flows, and glomerular permeabilities in the hydropenic Munich-Wistar rat, a strain with surface glomeruli. Because benzolamide decreases absolute proximal reabsorptive rate, the rate of delivery of tubular fluid to the distal nephron should be at least transiently increased and may reduce sngfr by activating the tubulo-glomerular feedback system. Sngfr fell from 29.2+/2.0 to 2.1+/3.1 nl/min (P less than 0.01) after benzolamide (group 1), a percentage reduction equal to kidney glomerular filtration rate and similar to sngfr obtained in collections from distal tubules. Separate studies (group 2) revealed that if transient increases in distal nephron delivery were prevented by insertion of a long oil block in proximal tubules before control, the decrease in sngfr was prevented (30.3+/1.0 vs. 30.3+/1.8 nl/min, P greater than 0.9). In paired "unblocked" nephrons in the same rats, sngfr fell in group 2 (33.0+/1.0 vs. 25.2+/2.3 nl/min, P less than 0.01). In "blocked" nephrons in which sngfr reduction was prevented, the rate of fluid leaving the proximal tubule increased from 16.9+/ to 23.1+/1.0 nl/min (P less than 0.01). In group 1 studies in which sngfr fell and transient increases in flow out of the last segment of the proximal tubule (distal delivery) (approximately equal to 8 nl/min) were not prevented, steady-state distal delivery was unchanged by benzolamide (13.9+/1.1 vs. 14.2+/2.2 nl/min). Also, sngfr returned toward control, pre-benzolamide values, when a proximal oil block was placed for 15 min and the rate of distal delivery reduced after benzolamide administration, which suggests that this activation was reversible. These data suggest that activation of tubulo-glomerular feedback by transient increases in distal delivery was responsible for decreases in sngfr. Analysis of all determinants of glomerular ultra-filtration revealed that the efferent mechanism leading to reduced sngfr after benzolamide was decreased nephron plasma flow (101+/13 vs. 66+/13 nl/min, P less than 0.01). Hydrostatic pressure and the glomerular permeability coefficient did not contribute to reductions in sngfr with benzolamide. Because the rate of distal delivery remained constant in spite of large changes in both sngfr and absolute proximal reabsorptive rate, it is suggested that the rate of distal delivery may be the physiologic entity that is regulated by the tubulo-glomerular feedback system via alterations in sngfr.

We have examined the response of directly and indirectly (stop-flow) measured glomerular capillary hydrostatic pressure (PGC) and single nephron glomerular filtration rate (SNGFR) to increases in late proximal tubular flow rate in hydropenic rats and rats in which angiotensin II (ANG II) and prostaglandin generation was reduced by 3- to 5-day pretreatment with converting enzyme inhibitor (MK-421) and meclofenamate. In control rats, PGC (48 +/- 2 mmHg) decreased 9 +/- 1 mmHg when 25 nl/min was added to late proximal flow in unobstructed tubules, and PGC decreased 9 +/- 1 mmHg when late proximal perfusion rate was increased from 0 to 40 nl/min, incrementally, in wax-blocked tubules. The turning point or half-maximal response for PGC was at perfusion rates of 23 +/- 2 nl/min. Stop-flow estimated PGC (47 +/- 1 mmHg = control) responses were nearly identical. SNGFR decreased from 30 +/- 1 to 21 +/- 1 nl/min with increased perfusion in control rats. In ANG II-prostaglandin-blocked rats, PGC and stop-flow pressure responses were completely eliminated, yet SNGFR response persisted (36.2 to 28.0 nl/min) but to a somewhat lesser extent. Both direct and indirect PGC decrease with increases in late proximal flow rate in untreated rats. Studies in ANG II-prostaglandin-blocked rats suggest that tubuloglomerular feedback SNGFR responses can occur without changes in PGC, possibly via parallel changes in afferent and efferent arteriolar resistances.

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.