Administration of a substituted adamantly-urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats

Jeffrey J Olearczyk , Jeffrey E Quigley , Bradford C Mitchell , Tatsuo Yamamoto , In-Hae Kim , John W Newman , Ayala Luria , Bruce D Hammock , John D Imig (1)

1 Pharmacology & Toxicology

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 using angiotensin II and a high salt diet. Hypertensive Goto-Kakizaki 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 Goto-Kakizaki rats, respectively. AUDA treatment did not alter blood glucose. Hypertension in Goto-Kakizaki rats resulted in a 17-fold increase in urinary albumin excretion that 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 and kidney cortex MCP-1 gene expression. Taken together, these data provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and type II diabetes.

Mots clés: Medicine

Jeffrey J Olearczyk, Jeffrey E Quigley, Bradford C Mitchell, Tatsuo Yamamoto, In-Hae Kim, et al.. Administration of a substituted adamantly-urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats. Clinical Science, 2008, 116 (1), pp.61-70. ⟨10.1042/CS20080039⟩. ⟨hal-00479425⟩