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Hum Gene Ther. 2012 Jul;23(7):688-99. doi: 10.1089/hum.2011.135. Epub 2012 Mar 29.

Delivery of AAV2-CYP2J2 protects remnant kidney in the 5/6-nephrectomized rat via inhibition of apoptosis and fibrosis.

Author information

1
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.

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.

PMID:
22260463
DOI:
10.1089/hum.2011.135
[Indexed for MEDLINE]

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