Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Kyung Mok Kim, Ki Wung Chung, Hyeong Oh Jeong, Bonggi Lee, Dae Hyun Kim, June Whoun Park, Seong Min Kim, Byung Pal Yu and Hae Young Chung _

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Oncotarget. 2018; 9:5588-5599. https://doi.org/10.18632/oncotarget.23652

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Abstract

Kyung Mok Kim1,*, Ki Wung Chung1,*, Hyeong Oh Jeong1, Bonggi Lee1,2, Dae Hyun Kim1, June Whoun Park1, Seong Min Kim1, Byung Pal Yu3 and Hae Young Chung1

1 Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea

2 Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea

3 Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

* These authors contributed equally to this work

Correspondence to:

Hae Young Chung, email:

Keywords: Aging; renal fibrosis; MMP2; A2M; extracellular matrix; Gerotarget

Received: July 27, 2017 Accepted: December 01, 2017 Published: December 24, 2017

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.


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