Epigenetic Regulation of the N-Terminal Truncated Isoform of Matrix Metalloproteinase-2 (NTT-MMP-2) and Its Presence in Renal and Cardiac Diseases

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.

Identification of biomarkers and prediction of upstream miRNAs in diabetic nephropathy

“…Renal fibrosis is one of the main causes of DN, which is characterized by the activation and proliferation of fibroblasts and the deposition of ECM ( 14 ). Matrix metalloproteinase-2(MMP2) play an important role in renal fibrosis and DN ( 15 ). Therefore, we investigated the effect of MMP2 activation on fibrotic pathways and cytokine characteristics.…”

“…In this context, we aimed to further explore the related genes involved in fibrosis, finally selected the target gene MMP2 for further research, explored the miRNAs acting on this gene, and find a new therapeutic target to improve DN. MMP2 plays a key role in the development of chronic kidney disease by remodeling the extracellular matrix, distorting the structure of the glomerular basement membrane, contributing to the development of tubulointerstitial fibrosis and leading to progressive kidney injury (15). The study found that the expression of MMP2 in renal tissue of DN patients increased (21), and the serum level of MMP-2 was significantly higher than that of normal healthy subjects (22).…”

“…MMP2 plays a key role in the development of chronic kidney disease by remodeling the extracellular matrix, distorting the structure of the glomerular basement membrane, contributing to the development of tubulointerstitial fibrosis and leading to progressive kidney injury ( 15 ). The study found that the expression of MMP2 in renal tissue of DN patients increased ( 21 ), and the serum level of MMP-2 was significantly higher than that of normal healthy subjects ( 22 ).…”

Potential roles of visfatin/NAMPT on endothelial dysfunction in preeclampsia and pathways underlying cardiac and vascular remodeling

“…Interestingly, increased oxidative stress and hypoxia were shown to induce the formation of a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) that remains intracellular in or near the mitochondria of cardiac tissue, which expression activates a pro-inflammatory, proapoptotic innate immune response (Lovett et al, 2012). Notably, insights into the epigenetic regulation of the latent promoter of NTT-MMP-2 located in the first MMP-2 intron, including its overlap with a putative active enhancer element, histone modifications, and binding sites for transcription factors which are known to cooperate in hypoxia-induced gene transcription are proposed elsewhere (Cruz et al, 2021). Finally, transfection of NTT-MMP-2 cDNA in cardiomyoblasts resulted in increased luciferase reporter activity for NF-κB (Lovett et al, 2012).…”

Epigenetic regulation of mitochondrial‐endoplasmic reticulum dynamics in kidney diseases

“…Malfunctioning of ER and mitochondria occurs as a result of stress factors such as pathogenic attacks, trauma, inflammatory response, or aberrant epigenetic modifications, and so forth. (Cruz et al, 2021; Sankrityayan et al, 2022). To maintain cellular homeostasis, these organelles interact with each other through membrane contact sites (MCSs) and are involved in the interchange of lipids, ions, or proteins required to maintain cellular integrity.…”