Premium
Differential Effects of Endothelin A and B Receptor Antagonism on Diabetes‐Induced Proteinuria, Glomerular Permeability, and Inflammation
Author(s) -
Saleh Mohamed A.,
Pollock Jennifer S.,
Pollock David M.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.812.1
Subject(s) - medicine , endocrinology , proteinuria , endothelin receptor , receptor , diabetes mellitus , chemistry , receptor antagonist , kidney , antagonist
Both selective ET A and combined ET A/B receptor antagonists can reduce proteinuria in diabetic nephropathy, but it is not clear that one type of drug would have an advantage over the other. The aim of this study was to elucidate receptor‐specific actions of ET A and ET B receptors in the activation of inflammatory mediators and increasing glomerular permeability to albumin (P alb ) in the diabetic kidney. Male Sprague‐Dawley rats were administered STZ; i.v., 65 mg/kg (H) or saline (sham, S). After 6‐wk of established hyperglycemia, a subset of animals (HA) received the ET A selective antagonist, ABT‐627, in the drinking water (5 mg/kg). Another subset (HA/B) received the nonselective ET A/B antagonist, A182086 , in the drinking water (10 mg/kg). After 1‐wk treatment, urine was collected to measure proteinuria, glomeruli were isolated by sieving techniques. P alb was determined from the change in glomerular volume induced by exposing glomeruli to oncotic gradients of albumin; plasma and glomerular concentrations of MCP‐1 and ICAM‐1 were determined by ELISA. Results indicate that ET A receptors mediate the defect in P alb and proteinuria elevation in STZ diabetes with little influence of the ET B receptor. However, blockade of ET B receptors eliminates the anti‐inflammatory effect of ET A receptor blockade suggesting an advantage of ET A selective antagonists over combined ET A/B receptor blockade in diabetes.Sham (S) Hyperglycemic (H) Hyperglycemic + ABT‐627 (HA) Hyperglycemic + A182086 (HA/B)Plasma sICAM‐1 (ng/ml) 6.50±3.24 21.87±2.25 * 11.07±4.51 20.26±0.73 * Plasma MCP‐1 (ng/ml) 3.54±0.58 12.24±2.63 * 14.08±1.42 ** 14.50±1.11 ** Glomerular sICAM‐1 (ng/mg protein) 12.00±1.83 34.31±6.64 ** 14.91±3.91 † 36.36±2.00 ** § Glomeralar MCP‐1 (ng/mg protein) 3.98±1.10 10.55±0.87 * 7.00±0.91 12.80±2.54 **Data are mean ± SEM (n=3–4).* P <0.05 vs. S,** P <0.01 vs. S,† P< 0.05 vs. H and§ P <0.05 vs. HA.Data are mean ± SEM (n=4). *** P< 0.001 vs. S, ‡ P< 0.05 vs. Before treatment.Data are mean ± SEM (n=4) *** P <0.001 vs. S, † P <0.05 vs. H