Selective ETA and combined ETA and ETB 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 ETA and ETB 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 ABT-627 (5 mg/kg/d), a selective ETA antagonist; A-182086 (10 mg/kg/d), a combined ETA/B antagonist; or vehicle for 1 week. Sham controls received STZ vehicle (saline). Hyperglycemia led to significant proteinuria, increased glomerular permeability to albumin (Palb), nephrinuria, and an increase in total matrix metalloprotease (MMPs) and transforming growth factor-beta 1 (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 Palb, nephrinuria, and total MMPs 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 ETA and combined ETA/B antagonists reduced proteinuria, glomerular permeability and restored glomerular filtration barrier components integrity, but only ETA selective blockade had anti-inflammatory and anti-fibrotic effects. We conclude that selective ETA antagonists are more likely to be preferred for treatment of diabetic kidney disease.
- Received January 6, 2011.
- Revision received April 5, 2011.
- Accepted April 5, 2011.
- The American Society for Pharmacology and Experimental Therapeutics