Platelet-activating factor alters glomerular barrier size selectivity for macromolecules in rats.
The effect of platelet-activating factor (PAF) on glomerular permeability to macromolecules was investigated in the isolated kidneys from normal male Sprague-Dawley rats perfused at constant pressure. Compared with basal values, infusion of PAF (10 nM final concentration) into the isolated kidneys induced a progressive and significant increase in protein excretion (6.7 +/- 2.7 vs. 40.7 +/- 10.4 micrograms/min, P less than 0.01), completely reversible 20 min after PAF infusion was discontinued (8.5 +/- 1.3 micrograms/min). In additional experiments, during PAF infusion the fractional clearance of small neutral dextrans (radius 24-48 A), defined as the ratio of the clearance of neutral dextrans to the clearance of creatinine, was comparable to preinfusion values, whereas fractional clearance of large dextrans (greater than 50 A) was significantly elevated (P less than 0.005) above preinfusion values. The specific PAF receptor antagonist L 652731 completely prevented the increased fractional clearance of large dextrans induced by PAF. Finally, lowering Ca2+ concentration in the perfusion medium from 2.5 to less than 0.1 mM markedly reduced proteinuria in isolated kidneys exposed to PAF (80.0 +/- 10.3, 42.8 +/- 3.1, and 22.0 +/- 7.6 micrograms/min, respectively, for 2.5, 1.25, and less than 0.1 mM). These results indicate that in isolated perfused kidneys 1) PAF-induced proteinuria is a functional phenomenon reversible on discontinuing PAF infusion, 2) PAF modifies glomerular size-selective properties by increasing transmural passage of large dextran molecules, and 3) PAF-induced change in glomerular permselective properties is dependent on Ca2+ concentration in the extracellular medium.
Perico
N
N
Mario Negri Institute for Pharmacological Research, Ospedali Riuniti di Bergamo, Italy.
Remuzzi
A
A
Dadan
J
J
Battaglia
C
C
Remuzzi
G
G
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003911:Dextrans / Q000493:pharmacokinetics; D005110:Extracellular Space / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D009994:Osmolar Concentration; D010477:Perfusion; D010539:Permeability; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains
D003911:Dextrans; D005663:Furans; D046911:Macromolecular Substances; D010972:Platelet Activating Factor; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; D002118:Calcium