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. This evidence concerns the gene MMP2 and heart disorder.