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Am J Physiol Renal Physiol. 2017 Jun 1;312(6):F1166-F1183. doi: 10.1152/ajprenal.00461.2016. Epub 2017 Mar 22.

An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: implications for acute kidney injury.

Author information

1
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
2
Department of Radiology, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California; and.
3
Department of Surgery, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
4
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California; david.lovett@ucsf.edu.

Abstract

Acute kidney injury (AKI) causes severe morbidity, mortality, and chronic kidney disease (CKD). Mortality is particularly marked in the elderly and with preexisting CKD. Oxidative stress is a common theme in models of AKI induced by ischemia-reperfusion (I-R) injury. We recently characterized an intracellular isoform of matrix metalloproteinase-2 (MMP-2) induced by oxidative stress-mediated activation of an alternate promoter in the first intron of the MMP-2 gene. This generates an NH2-terminal truncated MMP-2 (NTT-MMP-2) isoform that is intracellular and associated with mitochondria. The NTT-MMP-2 isoform is expressed in kidneys of 14-mo-old mice and in a mouse model of coronary atherosclerosis and heart failure with CKD. We recently determined that NTT-MMP-2 is induced in human renal transplants with delayed graft function and correlated with tubular cell necrosis. To determine mechanism(s) of action, we generated proximal tubule cell-specific NTT-MMP-2 transgenic mice. Although morphologically normal at the light microscopic level at 4 mo, ultrastructural studies revealed foci of tubular epithelial cell necrosis, the mitochondrial permeability transition, and mitophagy. To determine whether NTT-MMP-2 expression enhances sensitivity to I-R injury, we performed unilateral I-R to induce mild tubular injury in wild-type mice. In contrast, expression of the NTT-MMP-2 isoform resulted in a dramatic increase in tubular cell necrosis, inflammation, and fibrosis. NTT-MMP-2 mice had enhanced expression of innate immunity genes and release of danger-associated molecular pattern molecules. We conclude that NTT-MMP-2 "primes" the kidney to enhanced susceptibility to I-R injury via induction of mitochondrial dysfunction. NTT-MMP-2 may be a novel AKI treatment target.

KEYWORDS:

acute kidney injury; chronic kidney disease; innate immunity; matrix metalloproteinase-2; mitochondria

PMID:
28331061
PMCID:
PMC5495883
DOI:
10.1152/ajprenal.00461.2016
[Indexed for MEDLINE]
Free PMC Article

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