The Role of Variations of Inherited Properties of the Glomerulus in the Pathogenesis of Glomerulonephritis

Inherited glomerular properties have been investigated in two strains of rat chosen because one of them, Lewis is susceptible to Heymann nephritis whereas the other DA, is resistant. The glomerular properties examined were the charge on the glomerular basement membrane (GBM) and the mesangial uptake of circulating proteins. The former was studied by measuring the specific renal uptake of cationic IgG which was significantly less in Lewis rats. The deposition of cationic IgG on the GBM was significantly less in Lewis rats. The deposition of cationic IgG on the GBM 15 minutes after its administration, as judged by immunofluorescent studies, confirmed this finding. Interestingly, the specific hepatic and splenic uptake of cationic IgG at 15 minutes and the binding of Alcian blue (a cationic dye) to red cells, were all less in Lewis rats than DA rats. Therefore, the negative charge on all the cell and membrane surfaces examined was less in Lewis rats than DA rats. The second glomerular property, the mesangial uptake of circulating proteins, was studied by measuring the renal uptake of aggregated IgG. This was greater in DA rats than Lewis rats. The effect of these differences in glomerular properties in the expression of some animal models of glomerular disease was investigated. Lewis rats developed proteinuria following infusion of hexadimethrine, a polycation, into the renal artery whereas DA rats did not. This confirmed the functional significance of the measured difference in GBM charge between the two strains. On the other hand, DA rats developed more proteinuria following puromycin aminonucleoside which may have been due to greater mesangial uptake of the drug. The differences in susceptibility to Heymann nephritis in the Lewis strain was confirmed. Chronic serum sickness induced by cationic HSA led to capillary loop deposits in Lewis rats whereas DA rats had mesangial deposits even in control kidneys. Therefore, Lewis rats have lesser membrane and cell surface charge, a lower mesangial uptake of circulating proteins than DA rats and are more liable to develop proteinuria and capillary loop deposits. The clinical relevance of these findings was tested by examining the red cell charge of three groups of patients with idiopathic membranous glomerulopathy (IMN), minimal change nephropathy (MCN) and IgA nephropathy (IgAN) who were in clinical remission or who had proteinuria less than 2.2g/24 hours. MCN and IMN are associated with heavy proteinuria which rarely occurs in IgAN. IMN is associated with capillary loop deposits whereas IgAN is associated with mesangial deposits. The red cell charge was significantly greater in patients with IgAN than MCN or IMN but all three patient groups fell within the normal range. If red cell charge correlates with GBM charge in patients as it does in the two strains of rats, the similarities between the kidneys of patients with IMN and Lewis rats and between the kidneys of patients with IgAN and DA rats are striking. Prostaglandins and their precursors have been shown to have beneficial effects on human and animal glomerulopathies. Modulation of mesangial uptake by prostaglandins and their precursors was investigated. Release of prostacyclin by the aortas of Lewis rats was greater than the aortas of DA rats. Studies of the effect of prostanoids or mesangial uptake of circulating antigen (cationic IgG) showed that all polyunsaturated fatty acid diets and infusions of prostacyclin (PGI2) or PGE1 caused an increase in both strains of rats whatever the effect on the uptake by the whole kidney. No difference between the two strains was observed. This may have been due to increased glomerular production of angiotensin II which is known to increase mesangial uptake. Prostaglandins and precursors have been shown to increase mesangial uptake of antigen. Modulation of mesangial uptake by prostaglandins may offer a new approach to therapy of these nephropathies. The results of these studies show that the glomerulus is not simply a passive participant of systemic events but that its properties vary within strains and are important and previously unrecognised factors in the individual response to various forms of glomerular injury