An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: implications for acute kidney injury.
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.
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Carla S
CS
Ceron
Department of Radiology, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California; and.
Celine
C
Baligand
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Sunil
S
Joshi
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Shaynah
S
Wanga
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Patrick M
PM
Cowley
Department of Surgery, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Joy P
JP
Walker
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Sang Heon
SH
Song
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Rajeev
R
Mahimkar
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Anthony J
AJ
Baker
Department of Surgery, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California.
Robert L
RL
Raffai
Department of Radiology, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California; and.
Zhen J
ZJ
Wang
Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California; david.lovett@ucsf.edu.
David H
DH
Lovett
D058186:Acute Kidney Injury / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000367:Age Factors; D000818:Animals; D003324:Coronary Artery Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D007527:Isoenzymes; D007683:Kidney Tubular Necrosis, Acute / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000276:immunology / Q000648:ultrastructure; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000648:ultrastructure; D063306:Mitophagy; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction
D007527:Isoenzymes; D017382:Reactive Oxygen Species; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
acute kidney injury; chronic kidney disease; innate immunity; matrix metalloproteinase-2; mitochondria