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 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.

Cyclic stretch-induced TGF-β1 and fibronectin expression is mediated by β1-integrin through c-Src- and STAT3-dependent pathways in renal epithelial cells

“…Of the members of the Src kinase family, we have reported that mechanical stretch activates c-Src and enhances the activation of ERK1/2 in renal proximal tubular cells (1). Moreover, a variety of experimental studies implicate c-Src in the pathogenesis of progressive renal fibrosis (27,29,45). Additionally, numerous studies indicate that c-Src is critical for TGF-␤1-mediated renal fibrosis (7,23,48).…”

Estudo morfométrico de rins em felinos domésticos (Felis catus)

“…Como descrito por Slusarz et al (2013), tal confirmação serve também para humanos, uma vez que a incidência de doenças renais em indivíduos norte americanos, aumentou, proporcionalmente ao aumento da população acima de 65 anos.…”

“…As alterações morfológicas que levam a lesão e doença renal em felinos senis, também são descritas para outras espécies, como em caninos e em humanos, de acordo respectivamente com Lustoza & Kogika (2003) e Slusarz et al (2013).…”

“…A avaliação qualitativa do parênquima renal, que exibiu diferença entre os grupos, onde foi detectada uma predominância de fibras colágenas do tipo I nos animais dos grupos 1 e 2, e fibras colágenas do tipo III nos animais do grupo 3, permite avaliações com casos de ocorrência de fibrose renal, que é descrita como fator relacionado ao envelhecimento dos tecidos, e que decoore de alterações metabólicas relacionadas a alterações de metaloproteinas da matriz mesangeal (Slusarz et al 2013), e elevados níveis de endostatina (Lin et al 2014).…”

“…Para Slusarz et al (2013) o aumento da expressão de metaloproteínas do tipo 7 (MMPs-7) na matriz mesangeal, promoveu um aumento da expressão dos genes de coláge-no Col1a2 e Col3a1 em ratos acima de 16 meses de idade, sugestivos de um novo mecanismo de alterações na deposição de colágeno em decorrência do envelhecimento do tecido, o que pode contribuir para o desenvolvimento de fibrose levando a doença renal crônica.…”