Affiliation:
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
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.
Funder
Fellowship Grant from Ciencias sem Fronteiras
National Institute of Diabetes, Digestive and Kidney Disease/National Insitutes of Health
Kolff Student Fellowship Abroad Award, Dutch Kidney Foundation
American Heart Association Post-Doctoral Fellowship
National Institute of Diabetes, Digestive and Kidney Disease T32 Training Grant (Lovett)
Grant from Pusan National University School of Medicine
Department of Veterans Affairs Merit Review Award
American Heart Association Grant-in-Aid Award
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Heart Lung and Blood Institute NIH
National Research Foundadtion of Korea
Publisher
American Physiological Society
Cited by
15 articles.
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