The chemotactic factors responsible for complement-independent macrophage accumulation in immunecomplex diseases such as glomerulonephritis remain unknown. Fc receptors for IgG complexes are found on mesngial cells of the kidney, which produce the macrophage growth factor colony-stimulating factor 1 (CSF-1). We therefore investigated the possible stimulation of mesangial-cell expression of CSF-1 and the recently identified monocyte-specific chemoattractant protein 1 (MCP-1) by IgG complexes. IgG complexes, but not monomeric IgG or F(ab')2 fragments of IgG, rapidly (2-8 h) increased mRNA for both CSF-1 (10-fold) and MCP-1 (20-fold) in cultured mouse mesangial cells. The increase of mRNA for CSF-1 and MCP-1 was not reduced by either cytochalasin B or D, indicating that Fc receptor occupancy is sufficient for signaling and that phagocytosis is not required to elicit this response. IgG complexes also caused a 10-fold increase in the secretion of CSF-1 and a 3-to 5-fold increase in secretion of MCP-1 into the cell culture medium. The synthesis and release of CSF-1 and MCP-1 by mesangial cells as a consequence of Fc receptor occupancy may be responsible for macrophage recruitment and activation at sites of immune-complex deposition.

Localization of immune complexes (IC) to the mesangium may contribute to glomerular disease. Recently, we and others characterized Fc receptors (Fc gamma R) for IgG-IC on mesangial cells (MC). This study examines regulation of Fc gamma R by cAMP, interferon gamma (IFN-gamma) and by macrophage colony stimulating factor (CSF-1), an agent controlling Fc gamma R in leukocytes and generated by MC. Preincubation of MC (3rd to 6th subculture) with CSF-1, db-cAMP or IFN-gamma for two to 48 hours resulted in a time dependent (maximal 24 to 48 hrs) two- to threefold increase of specific [125I] IgG-IC binding to MC at 4 degrees C. The increase of Fc receptors induced by CSF-1, db-cAMP or IFN-gamma was confirmed by enhanced binding of the monoclonal anti-Fc receptor antibody 2.4G2 to MC. Uptake of IgG-IC at 37 degrees C was also enhanced in MC pretreated with CSF-1, db-cAMP or IFN-gamma. This indicates that the increase in binding for IgG-IC is associated with functional receptors. Immunoprecipitation of extracts of [125I] surface labeled MC with polyclonal anti-Fc gamma R-Ab followed by SDS-PAGE also showed increased amounts of [125I] Fc gamma R protein after pretreatment with CSF-1, db-cAMP or IFN-gamma. The pretreatment also enhanced staining of MC with anti-Fc gamma R-Ab by immunogold-silver enhancement technique. We conclude that MC express Fc gamma R for IgG-IC that can be regulated by CSF-1, cAMP and IFN-gamma, factors that may be important in glomerular immune injury.

Hyperlipidemia may contribute to the pathogenesis of glomerular sclerosis. We therefore studied binding and uptake of low density lipoprotein (LDL) by cultured rat mesangial cells. In addition effects of LDL on PGE2 synthesis and cell proliferation were determined. At 4 degrees C mesangial cells bound [125I] LDL in a time- and concentration-dependent manner with half-maximal binding observed at 5 micrograms/ml of LDL protein. Binding was blocked by excess unlabeled LDL and by heparin. Uptake (binding plus internalization) of LDL at 37 degrees C markedly exceeded binding at 4 degrees C, continued to increase even with longer periods of incubation, and showed no saturability, consistent with uptake of LDL by mesangial cells. Further evidence for LDL uptake by mesangial cells was obtained by use of the fluorescent probe 1,1'-dioactadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate-labeled LDL (Dil-LDL). Incubation of mesangial cells with Dil-LDL at 37 degrees C showed positive fluorescence for all mesangial cells, indicating uptake of the Dil-LDL. LDL had a biphasic effect on mesangial cell proliferation as determined by [3H] thymidine incorporation. LDL at 10 micrograms/ml enhanced [3H] thymidine uptake modestly, but significantly, whereas a progressive and marked inhibition occurred at LDL concentration from 100 to 500 micrograms/ml. While LDL at 10 and 100 micrograms/ml significantly stimulated PGE2 production, inhibition of PGE2 by meclofenamate did not influence the effects of LDL on [3H] thymidine incorporation. We conclude that mesangial cells show specific binding and uptake of LDL and that high concentrations of LDL markedly decrease mesangial cell proliferation. These findings may pertain to the pathogenesis of glomerular lesions in hyperlipidemia of renal disease.

The effect of acute and sequential volaemic changes on the gastroduodenal flow of saline was assessed in 23 anaesthetized dogs following two different experimental protocols. Hypervolaemia, by i.v. infusion of saline, induced a gradual decrease on gastroduodenal flow which amounted to 76% below control values (P less than 0.001) when volaemic expansion attained 5% of body weight. This effect was volume dependent (17% increase on gastroduodenal flow per volume of infused saline equivalent to 0.5% of body weight, P less than 0.001), lasted for at least 90 minutes after infusion was completed and was also obtained by expanding previously bled animals. Hypovolaemia due to bleeding was followed by an increase on gastroduodenal flow of about 88% above control values (P less than 0.05) when haemorrhage was equal to 3% of body weight. This effect was also volume dependent (23% increase on gastroduodenal flow per volume of blood shed equivalent to a 0.5% of body weight, P less than 0.01) and was reversed after blood volume was restored. These modifications in the resistance of the gastroduodenal segment to the flow of liquid due to acute volaemic changes suggest that the extracellular fluid volume modulates the contractile activity of the gastroduodenal portion of the gut possibly to set a gastroduodenal handling of liquid adequate to cope with volaemic imbalances.