title: Endothelin receptor A-specific stimulation of glomerular inflammation and injury in a streptozotocin-induced rat model of diabetes.
abstract: OBJECTIVE
  Activation of endothelin receptor-A (ET(A)) increases glomerular permeability to albumin (P(alb)) and elevates pro-inflammatory markers in hyperglycaemic rats.
  
  
  METHODS
  Male Sprague-Dawley rats were given streptozotocin (n = 32) or saline (sham; n = 32). Half of the animals in each group received the ET(A)-selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and P(alb) determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay.
  
  
  RESULTS
  At 3 and 6 weeks after streptozotocin injection, proteinuria was significantly increased compared with sham controls and significantly reduced by ABT-627 treatment. P(alb) was also increased at 3 and 6 weeks post-streptozotocin. ABT-627 had no effect on P(alb) or protein excretion in sham control rats. In glomeruli isolated from hyperglycaemic rats, incubation with BQ-123, a selective ET(A) antagonist, reduced P(alb), whereas BQ-788, a selective endothelin receptor-B antagonist had no effect (n = 6 rats per group, 5-8 glomeruli per rat). Glomerular and plasma content of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were significantly increased 6 weeks after streptozotocin (ELISA). ABT-627 attenuated these increases. After 6 weeks of hyperglycaemia, glomerular nephrin content was decreased with a concurrent increase in urinary nephrin excretion. ABT-627 prevented glomerular nephrin loss in hyperglycaemic rats (n = 5-8 rats per group; eight groups).
  
  
  CONCLUSIONS
  These observations support the hypothesis that endothelin-1, via the ET(A) receptor, directly increases P(alb), possibly via nephrin loss, as well as early inflammation in the hyperglycaemic rat.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30907-2500, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Saleh
authors.forename: E I
authors.initials: EI
authors.lastname: Boesen
authors.forename: J S
authors.initials: JS
authors.lastname: Pollock
authors.forename: V J
authors.initials: VJ
authors.lastname: Savin
authors.forename: D M
authors.initials: DM
authors.lastname: Pollock
mesh_terms: D000818:Animals; D000077868:Atrasentan; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D007118:Immunoassay; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000652:urine; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*
chemical_list: D065130:Endothelin A Receptor Antagonists; D008565:Membrane Proteins; D009842:Oligopeptides; D010880:Piperidines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; C113267:nephrin; C086539:BQ 788; D000077868:Atrasentan