MMP-9 gene deletion mitigates microvascular loss in a model of ischemic acute kidney injury

So Young Lee, Markus Hörbelt, Henry E. Mang, Nicole L. Knipe, Robert L. Bacallao, Yoshikazu Sado, Timothy A. Sutton

Research output: Contribution to journalArticle

35 Scopus citations

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 wellunderstood, 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.

Original languageEnglish (US)
Pages (from-to)F101-F109
JournalAmerican Journal of Physiology - Renal Physiology
Volume301
Issue number1
DOIs
StatePublished - Jul 1 2011

Keywords

  • Blood vessels
  • Chronic kidney disease
  • Ischemia
  • Kidney failure

ASJC Scopus subject areas

  • Physiology
  • Urology

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