title: MMP-9 gene deletion mitigates microvascular loss in a model of ischemic acute kidney injury.
abstract: Microvascular rarefaction following an episode of acute kidney injury (AKI) is associated with renal hypoxia and progression toward chronic kidney disease. The mechanisms contributing to microvascular rarefaction are not well-understood, although disruption in local angioregulatory substances is thought to contribute. Matrix metalloproteinase (MMP)-9 is an endopeptidase important in modifying the extracellular matrix (ECM) and remodeling the vasculature. We examined the role of MMP-9 gene deletion on microvascular rarefaction in a rodent model of ischemic AKI. MMP-9-null mice and background control (FVB/NJ) mice were subjected to bilateral renal artery clamping for 20 min followed by reperfusion for 14, 28, or 56 days. Serum creatinine level in MMP-9-null mice 24 h after injury [1.4 (SD 0.8) mg/dl] was not significantly different from FVB/NJ mice [1.5 (SD 0.6) mg/dl]. Four weeks after ischemic injury, FVB/NJ mice demonstrated a 30-40% loss of microvascular density compared with sham-operated (SO) mice. In contrast, microvascular density was not significantly different in the MMP-9-null mice at this time following injury compared with SO mice. FVB/NJ mice had a 50% decrease in tissue vascular endothelial growth factor (VEGF) 2 wk after ischemic insult compared with SO mice. A significant difference in VEGF was not observed in MMP-9-null mice compared with SO mice. There was no significant difference in the liberation of angioinhibitory fragments from the ECM between MMP-9-null mice and FVB/NJ mice following ischemic injury. In conclusion, MMP-9 deletion stabilizes microvascular density following ischemic AKI in part by preserving tissue VEGF levels.
authors: Div. of Nephrology/Dept. of Medicine, Indiana University School of Medicine, 950 West Walnut St., R-2, 202, Indianapolis, IN 46202, USA.
authors: So-Young
authors: SY
authors: Lee
authors: Markus
authors: M
authors: Hörbelt
authors: Henry E
authors: HE
authors: Mang
authors: Nicole L
authors: NL
authors: Knipe
authors: Robert L
authors: RL
authors: Bacallao
authors: Yoshikazu
authors: Y
authors: Sado
authors: Timothy A
authors: TA
authors: Sutton
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics; D012079:Renal Circulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D020780:Matrix Metalloproteinase 9