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20-HETE Analogs for Treating Renal Disease

MCW #1300

 

 Key Inventor

Richard Roman, PhD

 Background

Ischemic acute kidney injury contributes to kidney dysfunction and patient morbidity in a variety of clinical settings ranging from cardiovascular surgery to kidney transplantation. The renal injury following ischemia-reperfusion (I/R) results from multiple factors involving both changes in renal hemodynamics and injury to tubular epithelial cells. Ischemic insults may activate membrane bound phospholipase A2 which stimulates the release of arachidonic acid (AA) from membrane phospholipids. 20 Hydroxyeicosatetraenoic acid (20-HETE) is a product of CYP metabolism of AA and is produced in the kidney where it serves as an important regulator of vascular tone, renal blood flow (RBF), renal tubular sodium transport, and activates a number of intracellular signal transduction pathways involved in cell growth and survival. Dr. Roman’s lab examined the effects of stable 20-HETE analogs on the severity of experimental renal I/R injury in rats and explored their effect on renal sodium reabsorption and post-ischemic changes in renal hemodynamics.

 Description

Blocking the formation of 20-HETE with the compound HET0016, an inhibitor of 20-HETE synthesis, exacerbated renal dysfunction following I/R injury whereas treatment of rats with analogs of 20-HETE mitigated renal dysfunction and tubular injury when compared to control or HET0016-treated rats. Medullary blood flow (MBF), measured by laser-Doppler flowmetry, decreased to half of the baseline one hour after reperfusion in the control rats but the 20-HETE analog, 5,14-20-HEDGE, completely prevented this. Treatment of control animals with 5,14-20-HEDGE increased urine output and sodium excretion without altering their mean arterial pressure (MAP) or glomerular filtration rate (GFR). Although the mechanism of action remains to be determined, this data indicates that 20-HETE analogs promote sodium excretion in the absence of changes in MAP, RBF, or GFR and it prevents the post-ischemic fall in MBF.

The results of this study indicate that 20-HETE may exert protective effects in the kidney following I/R injury. The protection afforded by 20-HETE analogs in renal I/R injury may be due to preservation of renal medullary oxygen supply by inhibition of tubular sodium reabsorption and prevention of the post-ischemic fall in MBF. The finding that 5,14-20-HEDGE, mitigated renal I/R injury when administered after the ischemic period greatly increases the clinical relevance of this study. Overall, these findings provide a basis for the development of 20-HETE analogs as novel preventative or therapeutic agents in ischemic acute kidney injury.

 Features

1) Potential therapeutic for wide range of renal diseases including acute renal failure, proteinuria, glomerular disease, and polycystic kidney disease

2) Mitigates renal ischemia reperfusion when given before, or after, the ischemic interval

3) Large library of compounds available

4) World-wide patent coverage

 Stage of Development

This technology has been tested in vitro and in vivo. Pharmacokinetic data on these compounds is also available.

 Patents

This technology is covered by numerous US and international patents and patent applications covering composition of matter and methods for treating renal disease.

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MEDICAL COLLEGE OF WISCONSIN
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Summary Information

Patent Status:
11/229,241
PCT/US07/013740
+ 5 Foreign

Related Areas of Interest:
Kidney Systems


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