Clinical Investigation

Kidney International (1990) 38, 518–524; doi:10.1038/ki.1990.234

Angiotensin II receptor regulation in anti-glomerular basement membrane nephritis

Vicky Timmermans1, Philip W Peake1, John A Charlesworth1, Graham J Macdonald1 and Monika A Pawlak1

1Department of Medicine, Prince Henry Hospital, Sydney, Australia

Correspondence: Professor J A Charlesworth, Department of Medicine, Clinical Sciences Building, Prince Henry Hospital, Anzac Parade, Little Bay 2036, Australia.

Received 30 October 1989; Revised 2 April 1990; Accepted 6 April 1990.

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Abstract

Angiotensin II receptor regulation in anti-glomerular basement membrane nephritis. The expression of the glomerular receptor for angiotensin II (Ang II-R) was examined longitudinally following the induction of anti-glomerular basement membrane (GBM) nephritis in the rat. The specific aim of the project was to determine whether immunologically-induced glomerular injury led to significant abnormalities of the relationship between glomerular Ang II-R and its circulating ligand, Ang II. Scatchard analysis was used to measure Ang II-R on purified glomeruli at selected time intervals over two months following a single dose of sheep anti-rat GBM antibody. Corresponding values for plasma Ang II were determined. Receptor density fell to approximately 50% by 16 hours following the injection of antibody (control 96.4 plusminus 9.3 times 106; nephritic 52.6 plusminus 5.6 times 106 receptors/glomerulus; P < 0.001) and there was a corresponding threefold increase in plasma Ang II (control 21.0 plusminus 2.5; nephritic 66.6 plusminus 20.6 pg/ml; P < 0.01). However, this reduction in receptor binding could not be explained by the rise in plasma Ang II concentration, as effective blockade of the RAS by enalapril did not alter receptor expression (56.1 plusminus 4.6 times 106 receptors/glomerulus). Subsequently, a rise in receptor density and a corresponding fall in plasma Ang II were observed: three days after antibody administration, receptor concentration had increased significantly above control values (150.5 plusminus 11.9 times 106) while plasma Ang II was undetectable (that is, < 5 pg/ml). Ang II-R remained elevated for the next two weeks but returned to normal four to eight weeks after the administration of nephrotoxic antibody. Circulating Ang II levels remained low for the duration of the study. Administration of normal sheep globulin did not alter receptor density (88.7 plusminus 10.0 times 106). These studies demonstrate significant dissociation of plasma Ang II and its glomerular receptor during the course of anti-GBM nephritis in the rat. This indicates that Ang II-R is no longer under the control of components of the circulating RAS and may show an inappropriate response to variations in the level of circulating ligand. Such an abnormality could have an unfavorable influence on glomerular hemodynamics in the long-term.

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