Genetic disruption of soluble epoxide hydrolase is protective against streptozotocin-induced diabetic nephropathy.
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 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.
Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Guangzhi
G
Chen
Renfan
R
Xu
Yinna
Y
Wang
Peihua
P
Wang
Gang
G
Zhao
Xizhen
X
Xu
Artiom
A
Gruzdev
Darryl C
DC
Zeldin
Dao Wen
DW
Wang
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha
D051017:Apoptosis Regulatory Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid