Overexpression of MMP‐7 increases collagen 1A2 in the aging kidney

Physiological Reports

Anna Ślusarz³  LaNita A. Nichols³  Elizabeth A. Grunz-Borgmann³  Gang Chen¹  Adebayo D. Akintola¹  Jeffery M. Catania²  Robert C. Burghardt²  Jerome P. Trzeciakowski¹ 

[1] Department of Systems Biology & Translational Medicine, College of Medicine, Texas A&M University System Health Science Center;Department of Veterinary Integrated Biosciences, College of Veterinary Medicine, Texas A&M University;Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri

关键词: Aging;    collagen;    fibrosis;    MMP‐7;   

DOI  :  10.1002/phy2.90

来源: Wiley

【 摘 要 】

Abstract

The percentage of the U.S. population over 65 is rapidly increasing, as is the incidence of chronic kidney disease (CKD). The kidney is susceptible to age-dependent alterations in structure, specifically tubulointerstitial fibrosis that leads to CKD. Matrix metalloproteinases (MMPs) were initially characterized as extracellular matrix (ECM) proteinases; however, it is clear that their biological role is much larger. We have observed increased gene expression of several MMPs in the aging kidney, including MMP-7. MMP-7 overexpression was observed starting at 16 months, with over a 500-fold upregulation in 2-year-old animals. Overexpression of MMP-7 is not observed in age-matched, calorically restricted controls that do not develop fibrosis and renal dysfunction, suggesting a role in the pathogenesis. In order to delineate the contributions of MMP-7 to renal dysfunction, we overexpressed MMP-7 in NRK-52E cells. High-throughput sequencing of the cells revealed that two collagen genes, Col1a2 and Col3a1, were elevated in the MMP-7 overexpressing cells. These two collagen genes were also elevated in aging rat kidneys and temporally correlated with increased MMP-7 expression. Addition of exogenous MMP-7, or conditioned media from MMP-7 overexpressing cells also increased Col1A2 expression. Inhibition of protein kinase A (PKA), src, and MAPK signaling at p38 and ERK was able to attenuate the MMP-7 upregulation of Col1a2. Consistent with this finding, increased phosphorylation of PKA, src, and ERK was seen in MMP-7 overexpressing cells and upon exogenous MMP-7 treatment of NRK-52E cells. These data suggest a novel mechanism by which MMP-7 contributes to the development of fibrosis leading to CKD.

【 授权许可】

CC BY   
© 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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