title: Enhanced vascular chymase-dependent conversion of endothelin in the diabetic kidney.
abstract: BACKGROUND
  Diabetic nephropathy (DN) is associated with enhanced renal, plasma, and urinary endothelin (ET)-1 levels. Chymase cleaves Big ET-1 (1-38) to ET-1 (1-31), which is further cleaved by neutral endopeptidase to ET-1 (1-21). The current study tested the hypothesis that afferent arterioles (AA) of diabetic kidneys exhibit enhanced vasoconstrictor responses to chymase-dependent intrarenal ET formation compared to control kidneys.
  
  
  METHODS
  In situ juxtamedullary AA vasoconstrictor responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 (1-21) were performed in the absence and presence of chymase inhibition in type 2 diabetic db/db and control db/m mice studied under in vitro experimental conditions.
  
  
  RESULTS
  AA vasoconstrictor responses to Big ET-1 (1-38) were significantly enhanced in diabetic compared to control kidneys. In the presence of chymase inhibition (JNJ-18054478), AA vasoconstrictor responses of diabetic kidneys to Big ET-1 (1-38) were significantly less than the responses of control kidneys. AA diameters decreased similarly to ET-1 (1-21) in diabetic and control kidneys.
  
  
  CONCLUSIONS
  AA responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 in the absence of chymase enzymatic activity were significantly reduced in kidneys of diabetic compared to control mice, while the magnitude of the vasoconstriction to ET-1 (1-21) was not different. These data suggest that AA vasoconstriction produced by the chymase-dependent pathway is significantly greater in diabetic compared to control kidneys. We propose that intrarenal chymase-dependent ET-1 production contributes to the decline in function and progression to end-stage renal disease in patients with type 2 diabetes.
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Harrison-Bernard
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Bivona
keywords: Chymases; diabetic nephropathies; endothelin-1; kidney failure; vasoconstriction