Selective
endothelin A (ET(A)) and combined ET(A) and ET(B) receptor antagonists are being investigated for use in treating
diabetic nephropathy. However, the receptor-specific mechanisms responsible for producing the potential benefits have not been discerned. Thus, we determined the actions of ET(A) and ET(B) receptors on measures of glomerular function and renal
inflammation in the early stages of diabetic renal injury in rats through the use of selective and combined antagonists. Six weeks after
streptozotocin (STZ)-induced
hyperglycemia, rats were given 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic
acid (ABT-627) (5 mg/kg/day), a selective ET(A) antagonist; (2R,3R,4S)-4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluoro-4-methoxyphenyl)-1-(2-(N-propylpentylsulfonamido)ethyl)
pyrrolidine-3-
carboxylic acid hydrochloride (A-182086) (10 mg/kg/day), a combined ET(A/B) antagonist; or vehicle for 1 week.
Sham controls received STZ vehicle (saline).
Hyperglycemia led to significant
proteinuria, increased glomerular permeability to
albumin (P(alb)), nephrinuria, and an increase in total matrix
metalloprotease (
MMP) and transforming growth factor-β1 (TGF-β1) activities in glomeruli. Plasma and glomerular soluble
intercellular adhesion molecule-1 (sICAM-1) and
monocyte chemoattractant protein-1 (MCP-1) were elevated after 7 weeks of
hyperglycemia. Daily administration of both
ABT-627 and
A-182086 for 1 week significantly attenuated
proteinuria, the increase in P(alb), nephrinuria, and total
MMP and TGF-β1 activity. However, glomerular sICAM-1 and MCP-1 expression was attenuated with
ABT-627, but not
A-182086, treatment. In summary, both selective ET(A) and combined ET(A/B) antagonists reduced
proteinuria and glomerular permeability and restored glomerular filtration barrier component integrity, but only ET(A)-selective blockade had anti-inflammatory and antifibrotic effects. We conclude that selective ET(A) antagonists are more likely to be preferred for the treatment of
diabetic kidney disease.