Abstract
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.
Highlights
Matrix metalloproteinases (MMPs) are a large family of zinccontaining endopeptidases that participate in multiple cellular processes beyond extracellular matrix (ECM) remodeling and in kidney diseases (Tan and Liu, 2012; Parrish, 2017)
This perspective presents the findings about the discovery of the NTT-MMP-2 isoform, its functional and structural differences as compared with the FL-MMP-2 isoform, the alterations in the kidney of transgenic mice expressing the NTT-MMP-2 isoform, insights into the epigenetic regulation of the latent promoter located in the first intron of MMP2 gene that support the activation of the NTT-MMP-2 isoform, and highlights the role of the NTT-MMP-2 isoform in renal and cardiac diseases
We provide insights into the epigenetic regulation of the latent promoter located in the first intron of MMP-2, which support the activation of the NTT-MMP-2 isoform
Summary
Matrix metalloproteinases (MMPs) are a large family of zinccontaining endopeptidases that participate in multiple cellular processes beyond extracellular matrix (ECM) remodeling and in kidney diseases (Tan and Liu, 2012; Parrish, 2017). This NTT-MMP-2 isoform is enzymatically active but lacks the secretory sequence and the inhibitory propeptide, remains intracellular in the mitochondria, triggers mitochondrial-nuclear stress signaling via nuclear factorκβ (NF-κβ) and nuclear factor of activated T cells (NFAT), and induces innate immune response genes (Lovett et al, 2012) This perspective presents the findings about the discovery of the NTT-MMP-2 isoform, its functional and structural differences as compared with the FL-MMP-2 isoform, the alterations in the kidney of transgenic mice expressing the NTT-MMP-2 isoform, insights into the epigenetic regulation of the latent promoter located in the first intron of MMP2 gene that support the activation of the NTT-MMP-2 isoform, and highlights the role of the NTT-MMP-2 isoform in renal and cardiac diseases. Response by detaining HIF-1α in the nucleus (Ueda et al, 2008) These data further support the presence of the poised promoter located in the first intron of the MMP2 gene and suggest that it may be affected by a putative enhancer element activated by the binding of well-known hypoxia-induced transcription factors in the activation of the NTT-MMP-2 expression. FL-MMP-2 and NTT-MMP-2 are relevant targets of pharmacological intervention
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