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.
Highlights
The main characteristic of biological aging is defined as structural and functional degeneration due to the passage of time, and that degeneration tends to increase susceptibility to various diseases including diabetes, cardiovascular diseases, dementia, and other chronic diseases [1]
We investigated into the role of MMP2-A2M interaction on ECM accumulation during aging
The importance of MMP2-A2M interactions were derived from analysis of RNA-sequencing followed by protein–protein interaction (PPI) analysis in young, aged, and calorie restriction (CR) kidneys
Summary
The main characteristic of biological aging is defined as structural and functional degeneration due to the passage of time, and that degeneration tends to increase susceptibility to various diseases including diabetes, cardiovascular diseases, dementia, and other chronic diseases [1]. The major features of renal aging are glomerulosclerosis, tubular atrophy and interstitial fibrosis [5]. These pathological changes ameliorate renal function during aging. Recent study suggested that ECM accumulation is an early indicator of renal aging that can connect renal structure changes to functional decline [6]. Kidney aging indicators such as glomerular enlargement, podocyte hypertrophy, and mitochondrial abnormality have been delayed or even reversed by CR [7, 8]. CR has been shown to decrease age-associated renal fibrosis and chronic kidney diseases [10]. Biological processes how CR can retard excessive renal fibrosis needs to be demonstrated
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