Key result
The N-terminal truncated isoform of MMP-2 (NTT-MMP-2) is induced by hypoxia and oxidative stress, localizes to mitochondria, and contributes to renal and cardiac dysfunction.
Why the study?
A novel intracellular N-terminal truncated isoform of MMP-2 (NTT-MMP-2) was recently discovered, but its epigenetic regulation, presence, and pathophysiological role in renal and cardiac diseases needed clarification.
The novel intracellular NTT-MMP-2 isoform, induced by hypoxia and oxidative stress, plays a distinct pathophysiological role in renal and cardiac injury compared to full-length MMP-2, representing a potential therapeutic target.
NTT-MMP-2 may be a distinct cardiorenal target; leaves open whether selective inhibition alters outcomes in humans.
Several clinical and experimental studies have documented a compelling and critical role for the full-length matrix metalloproteinase-2 (FL-MMP-2) in ischemic renal injury, progressive renal fibrosis, and diabetic nephropathy. A novel N-terminal truncated isoform of MMP-2 (NTT-MMP-2) was recently discovered, which is induced by hypoxia and oxidative stress by the activation of a latent promoter located in the first intron of the MMP2 gene. This NTT-MMP-2 isoform is enzymatically active but remains intracellular in or near the mitochondria. In this perspective article, we first present the findings about the discovery of the NTT-MMP-2 isoform, and its functional and structural differences as compared with the FL-MMP-2 isoform. Based on publicly available epigenomics data from the Encyclopedia of DNA Elements (ENCODE) project, we provide insights into the epigenetic regulation of the latent promoter located in the first intron of the MMP2 gene, which support the activation of the NTT-MMP-2 isoform. We then focus on its functional assessment by covering the alterations found in the kidney of transgenic mice expressing the NTT-MMP-2 isoform. Next, we highlight recent findings regarding the presence of the NTT-MMP-2 isoform in renal dysfunction, in kidney and cardiac diseases, including damage observed in aging, acute ischemia-reperfusion injury (IRI), chronic kidney disease, diabetic nephropathy, and human renal transplants with delayed graft function. Finally, we briefly discuss how our insights may guide further experimental and clinical studies that are needed to elucidate the underlying mechanisms and the role of the NTT-MMP-2 isoform in renal dysfunction, which may help to establish it as a potential therapeutic target in kidney diseases.
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Cruz et al. (2021) conducted a review in Renal and cardiac diseases. NTT-MMP-2 was evaluated. The N-terminal truncated isoform of MMP-2 (NTT-MMP-2) is induced by hypoxia and oxidative stress, localizes to mitochondria, and contributes to renal and cardiac dysfunction.
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