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.
Mesangial handling of immune complexes may be important in immune injury. We examined whether vasoactive agents, independent of hemodynamic effects, could directly influence uptake of immunoglobulin G (IgG) complexes by mesangial cells (MC). Under basal conditions, MC took up more gold particles coated with IgG2b (P less than 0.05) than coated with IgG2a. Preincubation of MC with angiotensin II (ANG II) (5 x 10(-7) M) resulted in enhancement of uptake (P less than 0.05) of IgG2b-gold [7,578 +/- 968 counts per minute (cpm) per well], IgG2a-gold (4,566 +/- 295 cpm/well; P less than 0.01), and bovine serum albumin (BSA)-gold (2,532 +/- 66; P less than 0.05) when compared with respective controls (IgG2b-gold, 5,513 +/- 762 cpm/well; IgG2a-gold, 3,282 +/- 439; BSA-gold, 2,279 +/- 97). Cytochalasin B produced a significant reduction of uptake of IgG2b-gold (2,224 +/- 88 cpm/well) when compared with the uptake by control cells (3,711 +/- 287 cpm/well) (P less than 0.05). Pretreatment of MC with atrial natriuretic peptide (ANP, 10(-9) M) slightly decreased uptake of IgG-gold under basal conditions (P less than 0.05) and decreased the response to ANG II (P less than 0.05). Similarly, dopamine (DA, 10(-6) M) attenuated uptake of IgG2b-gold under basal (P less than 0.01) as well as ANG II-stimulated (P less than 0.01) states. ANP increased mesangial guanosine 3',5'-cyclic monophosphate (cGMP), DA, adenosine 3',5'-cyclic monophosphate (cAMP) content.(ABSTRACT TRUNCATED AT 250 WORDS)
Cocaine abuse has emerged as a major public health problem among young adults. Illicit use of cocaine has been associated with an increasing array of medical complications. Both traumatic and nontraumatic rhabdomyolysis, often complicated by acute renal failure, has recently been described following cocaine abuse. The present report describes our experience with 15 such patients and serves to further define the spectrum of muscle injury associated with cocaine abuse ranging from the incidental finding of elevated serum levels of muscle enzymes to acute renal failure. Those patients who developed renal failure experienced more severe rhabdomyolysis in association with trauma, seizures or hyperpyrexia.
We determined the effect of acute extracellular fluid volume changes on saline flow through 4 gut segments (ileocolonic, ileal, ileocolonic sphincter and proximal colon), perfused at constant pressure in anesthetized dogs. Two different experimental protocols were used: hypervolemia (iv saline infusion, 0.9% NaCl, 20 ml/min, volume up to 5% body weight) and controlled hemorrhage (up to a 50% drop in mean arterial pressure). Mean ileocolonic flow (N = 6) was gradually and significantly decreased during the expansion (17.1%, P<0.05) and expanded (44.9%, P<0.05) periods while mean ileal flow (N = 7) was significantly decreased only during the expanded period (38%, P<0.05). Mean colonic flow (N = 7) was decreased during expansion (12%, P<0.05) but returned to control levels during the expanded period. Mean ileocolonic sphincter flow (N = 6) was not significantly modified. Mean ileocolonic flow (N = 10) was also decreased after hemorrhage (retracted period) by 17% (P<0.05), but saline flow was not modified in the other separate circuits (N = 6, 5 and 4 for ileal, ileocolonic sphincter and colonic groups, respectively). The expansion effect was blocked by atropine (0.5 mg/kg, iv) both on the ileocolonic (N = 6) and ileal (N = 5) circuits. Acute extracellular fluid volume retraction and expansion increased the lower gastrointestinal resistances to saline flow. These effects, which could physiologically decrease the liquid volume being supplied to the colon, are possible mechanisms activated to acutely balance liquid volume deficit and excess.
CSF-1 stimulates the survival, proliferation, and differentiation of mononuclear phagocytes and may also play a role in placental development. The expression of CSF-1 and the CSF-1 receptor (CSF-1R) and their regulation were examined in cultures of mouse mesangial cells (MC). The concentration of CSF-1 in the medium of cultured MC increased linearly with time over 24 h. IFN-gamma stimulated and dibutyryl cyclic AMP inhibited CSF-1 production in a dose-dependent manner. MC expression of CSF-1 mRNA was shown by Northern blot analysis, and CSF-1 mRNA levels were increased within 4 h of IFN-gamma addition and inhibited within 4 h of dibutyryl cyclic AMP addition. Indirect immunofluorescence indicated that 90% of the untreated cultured MC expressed CSF-1. In addition, CSF-1R expression by MC was demonstrated by immunofluorescence with anti-receptor antibody, specific binding of [125I] CSF-1, and expression of the CSF-1R mRNA by Northern blot analysis. Thus, mouse MC, specialized pericytes of non-bone marrow origin, not only produce CSF-1 but also express receptors for CSF-1. The effects of CSF-1 on MC may be important in the control of immune function in the glomerulus.
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