dinoprost and Glomerulosclerosis--Focal-Segmental

This study tests the hypothesis that the age-associated reduction in glomerular filtration rate (GFR) and the presence of glomerulosclerosis renders effective renal plasma flow (ERPF) prostaglandin dependent. Ten healthy elderly volunteers were studied in a single-blind placebo-controlled manner using indomethacin to suppress the renal prostaglandins. There was no significant difference in ERPF or GFR following indomethacin when compared with placebo. These results suggest that blocking renal prostaglandins does not significantly alter ERPF or GFR in healthy elderly people.

Topics: Aged; Aging; Blood Flow Velocity; Dinoprost; Dinoprostone; Epoprostenol; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Male; Prostaglandins; Reference Values; Vasoconstriction

Oxidative stress has been proposed to play a crucial role in glomerulosclerosis, although its in vivo demonstration has proved taxing given the difficulty of inducing gene expression in specific renal cells. In this study, we examined whether the liver-directed expression of plasma platelet-activating factor acetylhydrolase (PAF-AH) would affect the glomerular pathophysiology in Imai rats, an animal model for glomerulosclerosis. Adenovirus-mediated liver-directed gene delivery of human PAF-AH resulted in a significant increase in plasma PAF-AH activity, which was detected almost exclusively on HDL. Histological examination of rats overexpressing PAF-AH showed not only the deposition of PAF-AH in mesangial cells, but also a reduction in hydroxynonenal and matrix protein content in the glomeruli. In situ hybridization analysis was negative for human PAF-AH mRNA in the kidney, while injection of HDL abundant in PAF-AH resulted in the deposition of PAF-AH in mesangial cells. Urine protein levels did not increase in rats overexpressing PAF-AH, while those of control rats increased significantly with age. This study provides direct evidence of the in vivo role of an enzyme that degrades lipid peroxides during the progression of glomerulosclerosis. Adenovirus-mediated extrarenal gene expression and lipoprotein-mediated glomeruli-targeted protein delivery promise to be a novel therapeutic approach to glomerulosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adenoviridae; Animals; Aorta; Creatinine; Dinoprost; Disease Models, Animal; Gene Transfer Techniques; Glomerulosclerosis, Focal Segmental; In Situ Hybridization; Kidney Glomerulus; Lipid Peroxides; Lipoproteins, HDL; Liver; Male; Mesangial Cells; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley

Eicosanoids are believed to play a role in the pathophysiology of several models of glomerular disease. The cyclooxygenase inhibitor indomethacin reduces proteinuria in patients with focal segmental glomerulosclerosis (FSGS) or other glomerular diseases. We have shown that sera of some patients with FSGS significantly increase glomerular albumin permeability (Palb) in an in vitro assay.. To determine the role of eicosanoids in the increased Palb caused by the FSGS factor, glomeruli were isolated from normal rats, preincubated with indomethacin, then incubated with FSGS serum or normal serum and Palb was calculated. To study the direct effect of individual eicosanoids on Palb, glomeruli were incubated with prostaglandin E2, prostaglandin F2alpha or a thromboxane A2 mimetic, and Palb was calculated. In the final set of experiments, normal glomeruli were preincubated with the thromboxane synthase inhibitor furegrelate, incubated with FSGS serum, and Palb was calculated.. Preincubation of isolated glomeruli with either the cyclooxygenase inhibitor indomethacin or the thromboxane synthase inhibitor furegrelate protected glomeruli from the increase in Palb caused by FSGS serum. Each of the three principal glomerular eicosanoids significantly increased Palb of isolated glomeruli.. These studies implicate a product of the cyclooxygenase pathway of arachidonic acid metabolism as mediating the increased Palb caused by FSGS serum in our in vitro assay and possibly the proteinuria seen in patients with FSGS.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Albumins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Benzofurans; Cell Membrane Permeability; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Enzyme Inhibitors; Glomerulosclerosis, Focal Segmental; Indomethacin; Kidney Glomerulus; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents

We have previously shown that aging is associated with increased lipid peroxidation, reductions in renal function, and increased glomerular sclerosis. The mechanism(s) responsible for these age-related changes are not clear. The purpose of the present studies was to determine if there was an increase in inducible nitric oxide synthase (iNOS) with aging, and if so, whether inhibition of iNOS would prevent aging injury by preventing free radical-mediated lipid peroxidation. iNOS protein expression in the kidney increased by approximately 90% by 24 months. Inhibition of iNOS by aminoguanidine (0.1% in drinking water) for 9 months, beginning at 13 months of age, reduced blood pressure, improved glomerular filtration rate by 70%, and renal plasma flow by 40%, whereas glomerular sclerosis was considerably reduced. Renal F2-isoprostanes and malondialdehyde levels, markers of oxidative stress and lipid peroxidation, were not reduced by aminoguanidine. Aminoguanidine also did not attenuate immunostaining for advanced glycosylation end products (AGE) in the kidneys. These findings suggest that aminoguanidine attenuates aging renal dysfunction by inhibiting a pathophysiologic function of iNOS that is independent of free radical-mediated lipid peroxidation or significant effects on AGE deposition.

Topics: Aging; Animals; Biomarkers; Blotting, Western; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; F2-Isoprostanes; Follow-Up Studies; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glycation End Products, Advanced; Guanidines; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renal Plasma Flow