In summary tail vein injection of

In summary, tail vein injection of mmLDL activated the ERK1/2 signaling pathway, leading to increased serum concentrations and increased vascular wall expression of ICAM-1 and VCAM-1, and may cause increased expression of vascular smooth muscle ETB receptors and the ETB receptor-mediated contractile function of blood vessels. Understanding the effect of mmLDL on ETB receptors and its mechanism can provide ideas for the prevention and treatment of cardiovascular disease.
Conflict of interest
Introduction In spite of the widespread use of cyclosporine A (CSA) as an immunosuppressant in organ transplantation and in control of several autoimmune diseases (Kovarik and Burtin, 2003), its nephrotoxic impact continues to present serious challenges in medicine. One key element in the initiation and progression of CSA nephrotoxicity is the imbalance between renal vasodilator and vasoconstrictor capacities, leading to renal ischemia and deterioration of renal function. CSA impairs renal responsiveness to prostacyclin (PGI2) (Miller, 2002) and nitric oxide (NO) (EL-Mas et al., 2004b). Reports from our laboratory showed that CSA, administered acutely or chronically, attenuates renal vasodilations caused by cholinergic (El-Mas et al., 2003, El-Mas et al., 2004b, El-Mas et al., 2011), β-adrenergic (El-Gowelli et al., 2011, El-gowilly et al., 2008), or adenosinergic activation (El-Mas et al., 2004a). Alternatively, CSA exacerbates responsiveness to endothelium-derived vasoconstrictors such as thromboxane A2 (Hardy et al., 2000), angiotensin II (Nishiyama et al., 2003), and endothelin (Cauduro et al., 2005). CSA upregulates endothelin mRNA in tubular epithelial Tetracaine HCl (Papachristou et al., 2009). CSA also upregulates TGF-β1 expression in tubular epithelial cells (Roos-van Groningen et al., 2006), which promotes tissue fibrosis (Wolf, 2006) and epithelial mesenchymal transition (Hazzan et al., 2011). Nonsteroidal antiinflammatory drugs (NSAIDs) with selective COX-2 inhibitory activity have been shown to exhibit renoprotective effects in some models of renal damage. For instance, celecoxib attenuates renal injury and inflammation in 5/6 nephrectomy rats (Fujihara et al., 2003). Moreover, celecoxib protects against cisplatin-induced oxidative stress and nephropathy (Suddek et al., 2011). Nevertheless, the mechanisms by which celecoxib elicits its renoprotective effect are not fully understood. The clinical relevance of this interaction is warranted because several arthritic conditions necessitate the combined use of CSA and NSAIDs such as rheumatoid arthritis, chronic polyarthritis, juvenile systemic lupus erythematosus and psoriatic arthritis (Ash et al., 2012, Cavalcante et al., 2011). Ironically, other NSAIDs such as naproxen and sulindac were found to cause more deterioration of renal function when used concomitantly with CSA. Pharmacokinetically, CSA has been shown to double the blood levels of diclofenac and impair renal function (Olyaei et al., 1999). In the current study, integrative and molecular studies were undertaken to investigate whether concurrent exposure to celecoxib protects against the CSA-induced nephrotoxicity in rats and potential underlying mechanisms. Accordingly, we explored the individual and combined effects of CSA and celecoxib on biochemical (serum urea and creatinine), inflammatory (IL-2), fibrotic (TGF-β1) and histopathological changes in the renal profile. More importantly, given that endothelin ETB receptors promote vasodilation (Davenport and Maguire, 2011) and enhance the clearance of circulating endothelin (Opitz and Ewert, 2006), we tested the hypothesis that the COX-2/ETB receptor pathway mediates the renoprotective effect of celecoxib against CSA nephropathy. This goal was accomplished by determining (i) the influence of ETB receptor blockade by BQ788 on renal consequences elicited by CSA or celecoxib, and (ii) immunohistochemical changes in the protein expression of COX-2 and ETB receptors in cortical and medullary tissues.