الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Concurrent use of CSA and NSAIDs became a common clinical practice in the management of some pathological conditions such as rheumatoid arthritis, chronic polyarthritis, juvenile systemic lupus erythematosus and psoriatic arthritis (Ash et al., 2012; Cavalcante et al., 2011). Because the single use of CSA or NSAIDs negatively influences renal and circulatory functions, the potential of developing exaggerated renal and cardiovascular consequences when the two medications are administered together is highly likely.
The current study was designed to evaluate the adverse renal and hemodynamic effects of the individual and combined exposure of rats to CSA and NSAIDs with variable COX-1/COX-2 selectivities. A series of integrative experimental studies, encompassing functional, cellular and molecular mechanisms, were utilized to elucidate the underlying mechanisms of CSA-NSAIDs interactions. The role of the ET-1/COX-2 pathway in the interaction was assessed by evaluating the effect of selective blockade of ET-A (atrasentan) or ET-B (BQ788) receptors on the CSA-NSAIDs interactions. Further, molecular mechanistic studies were pursued by measuring the immunohistochemical protein expression of COX-2 and ET-A and ET-B receptors in renal tissues. Changes in the renal inflammatory (IL-2 and TGF-β1) and oxidative (SOD, MDA, and GSH) profiles were also determined. A summary of the main findings and conclusions of the study is outlined below:
1. Chronic CSA caused significant elevations in blood pressure and deterioration of renal function. CSA facilitated ET/ET-A signaling in the renal arterioles with subsequent renal vasoconstriction, ischemia and oxidative stress. The oxidative imbalance provoked by CSA probably results in decreased NO bioavailability, and increased renal tissue stiffness, and elevated renal TGF-β1 and IL-2. Subsequently, the expression of renal COX-2 and the vasodilating antifibrogenic prostaglandins (PGE2 and PGI2) might be reduced. Together, these changes lead to (i) renal tubular atrophy and renal fibrosis, (ii) renal dysfunction manifested as increased serum urea and creatinine levels and (iii) hypertension.
2. The hypertensive response seen in rats treated chronically with CSA remained unaltered while the manifestations of nephrotoxicity were exaggerated when indomethacin was concurrently administered. Biochemical, receptor antagonist, and immunohistochemical protein expression studies showed that the ET-1/inflammatory cytokine pathway plays a fundamental role in the CSA/indomethacin interaction. Therefore, it is concluded that the COX-2 downregulation due to probably the overproduction of TGF-β1 is pivotal for triggering nephrotoxicity caused by CSA or indomethacin. The pharmacologic elimination of ET-A receptors might constitute a therapeutic strategy against renal damage caused by single or combined use of the two drugs.