title: Overexpression of MMP-7 Increases Collagen 1A2 in the Aging Kidney.
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 lead 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, and over a 500 fold up-regulation 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,Col1a2andCol3a1, 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 PKA, src, and MAPK signaling at p38 and ERK was able to attenuate the MMP-7 up-regulation 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.
authors.affiliation: Medical Pharmacology and Physiology, School of Medicine, University of Missouri.
authors.forename: Anna
authors.initials: A
authors.lastname: Oelusarz
authors.forename: Lanita A
authors.initials: LA
authors.lastname: Nichols
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grunz-Borgmann
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Adebayo D
authors.initials: AD
authors.lastname: Akintola
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Catania
authors.forename: Robert C
authors.initials: RC
authors.lastname: Burghardt
authors.forename: Jerome P
authors.initials: JP
authors.lastname: Trzeciakowski
authors.forename: Alan R
authors.initials: AR
authors.lastname: Parrish
keywords: Aging; Collagen; Fibrosis; MMP-7