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Chromatin changes trigger laminin genes dysregulation in aging kidneys.

ABSTRACT: Dysregulation of gene expression is a hallmark of aging. We examined epigenetic mechanisms that mediate aberrant expression of laminin genes in aging rat kidneys. In old animals, no alterations were found in the levels of abundant laminin mRNAs, whereas Lama3, b3, and c2 transcripts were increased compared to young animals. Lamc2 showed the strongest changes at the mRNA and protein levels. Lamc2 upregulation was transcriptional, as indicated by the elevated RNA polymerase II density at the gene. Furthermore, aging is associated with the loss of H3K27m3 and 5mC silencing modifications at the Lamc2 gene. Western blot analysis revealed no changes in cellular levels of H3K27m3 and cognate enzyme Ezh2 in old kidneys. Thus, the decrease in H3K27m3 at Lamc2 resulted from the re-distribution of this mark among genomic sites. Studies in kidney cells in vitro showed that reducing H3K27m3 density with Ezh2 inhibitor had no effect on Lamc2 expression, suggesting that this modification plays little role in gene upregulation in aging kidney. In contrast, treatment with DNA methylation inhibitor 2'-deoxy-5-azacytidine was sufficient to upregulate Lamc2 gene. We suggest that the loss of 5mC at silenced laminin genes drives their de-repression during aging, contributing to the age-related decline in renal function.

SUBMITTER: Denisenko O

PROVIDER: S-EPMC5990391 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Chromatin changes trigger laminin genes dysregulation in aging kidneys.

Denisenko Oleg O Mar Daniel D Trawczynski Matthew M Bomsztyk Karol K

Aging 20180501 5

Dysregulation of gene expression is a hallmark of aging. We examined epigenetic mechanisms that mediate aberrant expression of laminin genes in aging rat kidneys. In old animals, no alterations were found in the levels of abundant laminin mRNAs, whereas Lama3, b3, and c2 transcripts were increased compared to young animals. Lamc2 showed the strongest changes at the mRNA and protein levels. Lamc2 upregulation was transcriptional, as indicated by the elevated RNA polymerase II density at the gene. ...[more]

PMID: 29846172

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Project description:BackgroundThe mechanisms of kidney aging are not yet clear. Studies have shown that immunological inflammation is related to kidney aging. Toll-like receptors (TLRs) are one of the receptor types of the body's innate immune system. The function of the TLR system and the mechanisms by which it functions in renal aging remain unclear. In the present study, we, for the first time, systematically investigated the role of the TLR system and the inflammation responses activated by TLRs during kidney aging.MethodsWe used western blot and immunohistochemistry to systematically analyze the changes in the expression and activation of the endogenous TLR ligands HSP70 and HMGB1, the TLRs (TLR1-TLR11), their downstream signaling pathway molecules MyD88 and Phospho-IRF-3, and the NF-κB signaling pathway molecules Phospho-IKKβ, Phospho-IκBα (NF-κB inhibition factor α), NF-κBp65, and Phospho-NF-κBp65 (activated NF-κB p65) in the kidneys of 3 months old (youth group), 12 months old (middle age group), and 24 months old (elderly group) rats. We used RT-qPCR to detect the mRNA expression changes of the proinflammatory cytokines CCL3, CCL4, CCL5, CD80, TNF-α, and IL-12b in the rat renal tissues of the various age groups.ResultsWe found that during kidney aging, the HSP70 and HMGB1 expression levels were significantly increased, and the expression levels of TLR1, 2, 3, 4, 5, and 11 and their downstream signaling pathway molecules MyD88 and Phospho-IRF-3 were markedly elevated. Further studies have shown that in the aging kidneys, the expression levels of the NF-κB signaling pathway molecules Phospho-IKKβ, Phospho-IκBα, NF-κBp65, and Phospho-NF-κBp65 were obviously increased, and those of the proinflammatory cytokines CCL3, CCL4, CCL5, CD80, TNF-α, and IL-12b were significantly upregulated.ConclusionsThese results showed that the TLR system might play an important role during the kidney aging process maybe by activating the NF-κB signaling pathway and promoting the high expression of inflammation factors.

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Chromatin changes trigger laminin genes dysregulation in aging kidneys.

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Chromatin changes trigger laminin genes dysregulation in aging kidneys.

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