title: Delivery of AAV2-CYP2J2 protects remnant kidney in the 5/6-nephrectomized rat via inhibition of apoptosis and fibrosis.
abstract: The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), which are highly abundant in the kidney and considered renoprotective. Accumulating evidence suggests that EETs are important in regulating renal and cardiovascular function. Further, EETs have been confirmed to exert diverse biological activities including potent vasodilation; fibrinolytic properties; and antiinflammatory, antiapoptotic, and mitogenic effects. In the current study, we investigated the effects of overexpression of CYP2J2 via recombinant adeno-associated virus (rAAV) in protection against renal damage in a rat 5/6 nephrectomy (5/6-Nx) model of chronic renal failure. The rAAV-CYP2J2 gene delivery in vivo increased EET generation; attenuated the rise in blood pressure; and reduced the levels of proteinuria, serum creatinine, and blood urea nitrogen. Morphological analysis indicated that rAAV-CYP2J2 gene delivery reduced 5/6 nephrectomy-induced glomerular sclerosis, tubular dilatation, luminal protein cast formation, and tubulointerstitial fibrosis. rAAV-CYP2J2 gene delivery also significantly lowered collagen I and IV deposition, as well as renal cell apoptosis detected by TUNEL staining, caspase-3 activity, and the loss of mitochondrial membrane potential (ΔΨ(m)). Furthermore, rAAV-CYP2J2 gene delivery regulated the level of protein expression including transforming growth factor (TGF)-β(1)/SMADs; matrix metalloproteinases (MMPs); mitogen-activated protein kinases (MAPKs); and apoptosis-related proteins Bax, Bcl-2, and Bcl-x(L). Together, these findings demonstrated that rAAV-CYP2J2 gene delivery can protect remnant kidney against renal injury in 5/6-Nx rats by inhibiting apoptosis and fibrosis via regulation of protein expression including TGF-β(1)/SMADs, MMPs, MAPKs, and apoptosis-related proteins.
authors.affiliation: Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Ling
authors.initials: L
authors.lastname: Tu
authors.forename: Xuguang
authors.initials: X
authors.lastname: Li
authors.forename: Shenglan
authors.initials: S
authors.lastname: Yang
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xizhen
authors.initials: X
authors.lastname: Xu
authors.forename: Peihua
authors.initials: P
authors.lastname: Wang
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000652:urine; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D003094:Collagen / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics*; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000473:pathology / Q000628:therapy* / Q000652:urine; D051785:Smad Proteins / Q000378:metabolism
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D011994:Recombinant Proteins; D051785:Smad Proteins; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; C067407:14,15-episulfide eicosatrienoic acid; D000090762:Cytochrome P-450 CYP2J2; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D015126:8,11,14-Eicosatrienoic Acid