8-11-14-eicosatrienoic-acid and Fibrosis

Cardiac remodeling is one of the most common cardiac abnormalities and associated with a high mortality in chronic renal failure (CRF) patients. Apocynin, a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been showed cardio-protective effects. However, whether apocynin can improve cardiac remodeling in CRF and what is the underlying mechanism are unclear. In the present study, we enrolled 94 participants. In addition, we used 5/6 nephrectomized rats to mimic cardiac remodeling in CRF. Serum levels of epoxyeicosatrienoic acids (EETs) and its mainly metabolic enzyme-soluble epoxide hydrolase (sEH) were measured. The results showed that the serum levels of EETs were significantly decreased in renocardiac syndrome participants (P < 0.05). In 5/6 nephrectomized CRF model, the ratio of left ventricular weight / body weight, left ventricular posterior wall thickness, and cardiac interstitial fibrosis were significantly increased while ejection fraction significantly decreased (P < 0.05). All these effects could partly be reversed by apocynin. Meanwhile, we found during the process of cardiac remodeling in CRF, apocynin significantly increased the reduced serum levels of EETs and decreased the mRNA and protein expressions of sEH in the heart (P < 0.05). Our findings indicated that the protective effect of apocynin on cardiac remodeling in CRF was associated with the up-regulation of EETs. EETs may be a new mediator for the injury of kidney-heart interactions.

Topics: 8,11,14-Eicosatrienoic Acid; Acetophenones; Aged; Angiotensin II; Animals; Cardio-Renal Syndrome; Cardiotonic Agents; Cell Line; Disease Models, Animal; Epoxide Hydrolases; Female; Fibrosis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocytes, Cardiac; Rats, Sprague-Dawley; Stroke Volume; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

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.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Apoptosis; Blood Pressure; Collagen; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Dependovirus; Fibrosis; Gene Transfer Techniques; Genetic Therapy; Kidney; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinases; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic; Smad Proteins