Pretreatment with nebivolol attenuates level and expression of matrix metalloproteinases in a rat model of renal ischaemia–reperfusion injury

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Matrix metalloproteinases (MMPs) are endopeptidases that are involved in remodelling of extracellular matrix (ECM) and degradation of bioactive proteins. The substrates for MMPs other than ECM proteins constitute cell adhesion molecules (cadherins and integrins), growth factors and their receptors (TGF‐β, FGF‐R1). Mostly they are secreted as proMMPs and activation depends on cleavage of the prodomain by plasmin or other MMPs.1 Depending on domain organization and substrate type, MMPs are subgrouped into collagenases, gelatinases, stromelysins, and membrane‐type MMPs.2 Gelatinases (MMP‐2 and‐9) cleave the gelatins (denatured collagens) and laminin, as well as some chemokines. MMP‐2 also activates MMP‐1 and ‐9 by cleaving their prodomains.1
The expression of MMPs and its inhibitors [tissue inhibitors of matrix metalloproteinases (TIMPs)] in renal tissue is not well characterized. However, MMP‐2 is expressed in the glomerulus and proximal tubules of rats, MMP‐9 expression is mainly confined to glomeruli, although expression in the proximal and distal tubules of the monkey has been demonstrated.3 Recent data suggests the role of MMPs in pathophysiology of IRI, one of the major causes of acute kidney injury (AKI) in certain clinical situations.2 The pathophysiology may involve a complex interaction between vascular endothelium, inflammation, and tubular injury. Upregulation of MMPs results in degradation of renal microvascular matrix causing modulation of renal microvascular permeability, induction of apoptosis and necrosis, and consequently aggravation of tubular injury during IRI.1 These effects can be attributed to increased production of reactive oxygen species (ROS) in the areas of ischaemia and reperfusion.6 Inhibition of matrix metalloproteinases has been shown to reduce IRI in renal murine models.2 Treatment with β‐adrenergic blockers with anti‐oxidant properties attenuated hypertension‐induced increases in cardiac MMP‐2 levels, and inhibited MMP activity upregulation in two‐kidney one‐clamp induced hypertension in rats.8 Nebivolol, a third generation β1‐adrenergic receptor blocker with the capability to release NO from endothelium, has been shown to attenuate detrimental effects of pro‐oxidant and inflammatory mechanisms involving tissue growth factor‐β (TGF‐β) and MMPs in renovascular hypertension.10
In this study, we hypothesized that nebivolol may ameliorate AKI by decreasing MMP‐2 and ‐9 quantity and expression and thus prevent renal injury caused by IRI.
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