Genetic disruption of soluble epoxide hydrolase is protective against streptozotocin-induced diabetic nephropathy

Abstract

Cytochrome P-450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play important roles in regulating cardiovascular functions. The anti-inflammatory, antiapoptotic, proangiogenic, and antihypertensive properties of EETs suggest a beneficial role for EETs in diabetic nephropathy. Endogenous EET levels are maintained by a balance between synthesis by CYP epoxygenases and hydrolysis by epoxide hydrolases into physiologically less active dihydroxyeicosatrienoic acids. Genetic disruption of soluble epoxide hydrolase (sEH/EPHX2) results in increased EET levels through decreased hydrolysis. This study investigated the effects of sEH gene disruption on diabetic nephropathy in streptozotocin-induced diabetic mice. Streptozotocin-induced diabetic manifestations were attenuated in sEH-deficient mice relative to wild-type controls, with significantly decreased levels of Hb A1c, creatinine, and blood urea nitrogen and urinary microalbumin excretion. The sEH-deficient diabetic mice also had decreased renal tubular apoptosis that coincided with increased levels of antiapoptotic Bcl-2 and Bcl-xl, and decreased levels of the proapoptotic Bax. These effects were associated with activation of the PI3K-Akt-NOS3 and AMPK signaling cascades. sEH gene inhibition and exogenous EETs significantly protected HK-2 cells from TNFα-induced apoptosis in vitro. These findings highlight the beneficial role of the CYP epoxygenase-EETs-sEH system in the pathogenesis of diabetic nephropathy and suggest that the sEH inhibitors available may be potential therapeutic agents for this condition.

20-HETE and EETs in Diabetic Nephropathy: A Novel Mechanistic Pathway

“…Moreover, genetic disruption of sEH in STZ-induced diabetic mice show significant decreased levels of creatinine, BUN and urinary microalbumin excretion. Also, sEH-deficient diabetic mice showed reduced kidney injury [55]. These data indicate a role for EETs in the biology of proximal tubular epithelial cells.…”

Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

“…We and others have recently demonstrated that decreased EETs availability in streptozotocininduced diabetic mice was associated with a marked degree of renal injury and apoptosis and this effect was significantly reduced by increased EETs availability via the inhibition of sEH [9,17]. Inhibition of sEH also reduces hyperglycaemia and pancreatic β-cell islet apoptosis and increases insulin secretion in steptozotocin-induced Type 1 diabetes [18].…”

A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat

“…COX-2 inhibition reduced renal injury in pre-clinical diabetic models including type 2 diabetic ZDF rat by decreasing glomerular and tubulointerstitial injury mediators in the kidney [18,19]. Apart from the COX-2 pathway, sEH pathway of arachidonic acid metabolism also contributes to the pathophysiology of diabetic kidney injury, and sEH inhibition ameliorated experimental diabetic nephropathy [40,48,49]. These earlier reports along with our data in the present study provide convincing evidence that in type 2 diabetic fatty ZDF rats the novel dual acting COX-2/sEH inhibitor PTUPB prevented the diabetic kidney injury by concurrently acting on COX-2 and sEH pathways.…”