Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats.
Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto-Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118+/-2 mmHg to 182+/-20 and 187+/-6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.
Olearczyk
Jeffrey J
JJ
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA.
Quigley
Jeffrey E
JE
Mitchell
Bradford C
BC
Yamamoto
Tatsuo
T
Kim
In-Hae
IH
Newman
John W
JW
Luria
Ayala
A
Hammock
Bruce D
BD
Imig
John D
JD
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000652:urine; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007328:Insulin / Q000097:blood; D007850:Lauric Acids / Q000627:therapeutic use* / Q000652:urine; D008055:Lipids / Q000097:blood; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D000959:Antihypertensive Agents; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D007850:Lauric Acids; D008055:Lipids; D016328:NF-kappa B; D004851:Epoxide Hydrolases; D000218:Adamantane