Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 303, Issue 5, Pages E563-E575Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00591.2011
Keywords
soluble epoxide hydrolase gene disruption; hk-2 cells; diabetic nephropathy; epoxyeicosatrienoic acids
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Funding
- National Basic Research Program (973) [2012CB517801]
- NSFC [30930039, 30700377]
- Wuhan City grant
- National Institutes of Health, National Institute of Environnmental Health Sciences [Z01 ES-025034]
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Chen G, Xu R, Wang Y, Wang P, Zhao G, Xu X, Gruzdev A, Zeldin DC, Wang DW. Genetic disruption of soluble epoxide hydrolase is protective against streptozotocin-induced diabetic nephropathy. Am J Physiol Endocrinol Metab 303: E563-E575, 2012. First published June 26, 2012; doi:10.1152/ajpendo.00591.2011.-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 A(1c), 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 TNF alpha-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.
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