MMP2-A2M interaction increases ECM accumulation in aged rat kidney and its modulation by calorie restriction

Abstract

Age-associated renal fibrosis is related with renal function decline during aging. Imbalance between accumulation and degradation of extracellular matrix is key feature of fibrosis. In this study, RNA-sequencing (RNA-Seq) results based on next-generation sequencing (NGS) data were analyzed to identify key proteins that change during aging and calorie restriction (CR). Among the changed genes, A2M and MMP2, which are known to interact, exhibited the highest between centrality (BC) and degree values when analyzed by protein–protein interaction (PPI). Both mRNA and protein levels of MMP2 and A2M were increased during aging. Furthermore, the interaction between MMP2 and A2M was verified by immunoprecipitation and immunohistochemistry. MMP2 activity was further measured under the presence or absence of A2M-MMP2 interaction. MMP2 activity, which was increased under the absence of A2M-MMP2 interaction, was significantly decreased under the presence of interactions in aged kidney. We further hypothesized that the interaction between A2M-MMP2 played a role in the inactivation of MMP2 leading to accumulation of ECM including collagen type I and IV. Aged kidney showed highly accumulated MMP2 substrate proteins despite of increased MMP2 protein expression and CR blunted these accumulation. Additional in vivo analysis revealed that the signal transducer and activator of transcription (STAT) 3 transcriptional factor was significantly increased thus increasing A2M expression during aging. STAT3 activating cytokines were also highly increased in aged kidney. In conclusion, the results of the present study indicate that A2M-MMP2 interaction has a role in age-associated renal ECM accumulation and in the suppression such fibrosis by CR.

GFAP alternative splicing regulates glioma cell–ECM interaction in a DUSP4‐dependent manner

“…5 I ). In addition, in both of the GFAP‐α‐KO clonal lines, expression of α‐2‐macroglobulin ( A2M ) that binds and inhibits the active form of MMP2 (63) was strongly decreased, and expression was even mostly below detection (Fig. 5 J ).…”

Matrix Metalloproteinases in Diabetic Kidney Disease

“…MMP knockout mice models have shown increased fibrosis and accelerated kidney disease progression [25]. In contrast, several reports have shown that upregulation of MMPs promote fibrosis [5,[26][27][28] maybe due to interaction with overexpressed TIMPs [27,29] or due to the capacity of MMP degradation products to induce EMT [5,30]. In a study performed by Tan et al, they exposed murine tubular epithelial cells to an activated macrophage conditioned medium.…”

Intrarenal Renin–Angiotensin System Involvement in the Pathogenesis of Chronic Progressive Nephropathy—Bridging the Informational Gap Between Disciplines

“…25 –27 Age-related dysregulation of renal extracellular matrix (ECM) in rats has been shown to be associated with the loss of epigenetic gene silencing as well as with decreased matrix metallopeptidase 2 activity. 28 –30 However, it is difficult to determine whether alterations to the membrane are actually causal or simply an effect of early damage at the tubulointerstitial interface. Immunochemical investigations have revealed neither immune complexes nor serum antibody are responsible for basement membrane thickening, and serum from rats with advanced CPN are negative for immunoglobulin G (IgG) or IgM antibodies to kidney antigens.…”