Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2 þ / þ ) mice by 30, 60, 90, and 120 min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2 À/À ) mice and MMP-2 þ / þ mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2 þ / þ mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 h, peaked at 6 h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24 h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6 h and severity of AKI at 24 h increased depending on the duration of ischemia between 30 and 120 min. However, the kidneys of MMP-2 À/À mice showed minimal ATI; serum creatinine 24 h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24 h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemiareperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI. KEYWORDS: acute kidney injury; acute tubular injury; ischemia/reperfusion; MMP-2; MMP-9; MMP inhibitor Ischemia-reperfusion acute kidney injury (AKI) remains a major cause of morbidity and mortality.1-5 The pathophysiology of AKI is complex; the initial ischemia and reperfusion events rapidly lead to energy loss, which ultimately triggers a wide and intricately linked cascade of tubular epithelial cell death pathways. Over the past decade, various molecular mechanisms have been implicated, including activation of Ca 2 þ -dependent proteases or other enzymes, oxidative stress, and even programmed cell death signals, such as apoptosis. [6][7][8] In addition to these primarily intracellular events, evidence for the importance of intercellular signaling is beginning to emerge, all cells in the renal tubular and microvasculature are also affected, not just tubular epithelial cells.6-10 Renal tubulovascular perturbations in AKI lead to tubular damage, back leak, obstructive cast formation, leukocyte infiltration, and altered renal microvascular function that contribute to the development of AKI over hours or days after ischemia-reperfusion.Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases responsible for extracellular matrix turnover, as well as degradation of bioactive proteins. 11,12 This family includes collagenases, gelatinases, stromelysins, and membranetype MMPs. Recently, MMPs, especially gelatinases (MMP-2 and MMP-9) have been demonstrated to have major roles i...

Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.

We investigated the effect of a peroxisome proliferator-activated receptor alpha (PPARα) agonist ophthalmic solution in wound healing using a rat corneal alkali burn model. After instillation of a selective agonist of PPARα, fenofibrate, onto the burned cornea, PPARα-positive cells were observed in vascular endothelial cells, and there was upregulation of mRNA of PPARα in corneal stroma. Fenofibrate suppressed expression of neutrophils and macrophages during the early phase, and development of neovascularization and myofibroblast generation during the late phase. Fenofibrate reduced not only mRNA expression of vascular endothelial growth factor-A but also angiopoietin-1 and angiopoietin-2. Furthermore, fenofibrate suppressed scar formation by reducing type III collagen expression. These data suggest that a PPARα agonist ophthalmic solution might be a new strategy for treating corneal wounds through not only anti-inflammatory effects but also by preventing neovascularization.

Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro-and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-␥, tumor necrosis factor-␣, and interleukin-12.