Submitted to: Trade Journal Publication
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/20/2009
Publication Date: 1/1/2010
Publication URL: www.ncbi.nlm.nih.gov/pmc/articles/PMC2590620/pdf/nihms-55919.pdf
Citation: Olearczyk, J.J., Quigley, J.E., Mitchell, B.C., Yamamoto, T., Kim, I., Newman, J.W., Luria, A., Hammock, B.D., Imig, J.D. 2010. ADMINISTRATION OF A SUBSTITUTED ADAMANTLY-UREA INHIBITOR OF THE SOLUBLE EPOXIDE HYDROLASE PROTECTS THE KIDNEY FROM DAMAGE IN HYPERTENSIVE GOTO-KAKIZAKI RATS. Trade Journal Publication. 10.1042/CS20080039. Interpretive Summary: Hypertension and type II diabetes are co-morbid diseases that lead to the development of renal damage and recent reports suggest that soluble epoxide hydrolase inhibitors provide protection from renal damage. Based on these reports, we hypothesized that the soluble epoxide hydrolase inhibitors could also prevent renal damage associated with hypertension and diabetes. To this end, we induced hypertension in spontaneously diabetic Goto-Kakizaki rats (GK) using angiotensin II and a high salt diet. The hypertensive rats were then treated with either a soluble epoxide hydrolase inhibitor, or its vehicle, for two weeks in the drinking water. While the sEH inhibitor did not prevent the rise in blood pressure or plasma glucose, it was able to reduce the associated urinary albumin excretion. Moreover, histology showed this treatment reduced the glomerular and tubular damage characteristic of nephropathy seen in this animal model of kidney disease. This reduction was also associated with a reduced level of macrophage infiltration into these tissues, and reduced kidney expression and excretion of monocyte chemoattractant protein 1. Taken together, these data provide evidence that sEH inhibition can slow the progression of nephropathy associated with hypertension and type II diabetes
Technical Abstract: Hypertension and type II diabetes are co-morbid diseases that lead to the development of nephropathy. Soluble epoxide hydrolase (sEH) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects the kidney from the development of nephropathy associated with hypertension and type II diabetes. Hypertension was induced in spontaneously diabetic Goto-Kakizaki rats (GK) using angiotensin II and a high salt diet. Hypertensive GK rats were treated for two weeks with either AUDA or its vehicle added to drinking water. 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 characteristic of nephropathy. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of monocyte chemoattractant protein 1 (MCP-1) and kidney cortex MCP-1 gene expression. Taken together, these data provide evidence that sEH inhibition with AUDA attenuates the progression of nephropathy associated with hypertension and type II diabetes.