Role of abnormally high transmural pressure in the permselectivity defect of glomerular capillary wall: a study in early passive Heymann nephritis.

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Abstract
To explore the mechanism of glomerular permselectivity defect in passive Heymann nephritis, an experimental model of human membranous glomerulopathy, Munich-Wistar rats were subjected to both micropuncture assessment of glomerular hemodynamics and whole kidney clearance measurements of graded size dextrans 10 days after injection of sheep anti-rat tubular antigen (anti-Fx1A). Compared with normal control rats, anti-Fx1A-treated animals were characterized by marked proteinuria (65 +/- 8 micrograms/min versus 6 +/- 1, p less than 0.001), markedly and significantly higher glomerular transcapillary hydraulic pressure difference (40 +/- 1 mm Hg versus 33 +/- 1, p less than 0.001), depressed ultrafiltration coefficient and impaired glomerular size-selective function as determined by fractional clearance of dextrans. Calculation of membrane parameters based on a recently defined heteroporous membrane model revealed abnormally high availability of non-size selective, large pore pathways in the glomerular capillary wall of the rats with passive Heymann nephritis. To ascertain the role of the altered hemodynamic pattern in the observed defect in the size-selective function of the glomerular capillary wall, glomerular transcapillary hydraulic pressure difference was manipulated experimentally in these proteinuric rats by intra-aortic infusion of acetylcholine or angiotensin II. These agents respectively suppressed and augmented glomerular transcapillary hydraulic pressure difference and brought about a decline of and a further rise in fractional clearance of larger dextrans along with parallel changes in both urine protein excretion rate and availability of nonselective channels. These results indicate that the permselectivity defect in passive Heymann nephritis is attributable, at least in part, to impaired size selectivity of the glomerular capillary wall caused by a prevailing abnormally high transcapillary hydraulic pressure difference.