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Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

Imai R, Asai K, Hanai J, Takenaka M - Aging (Albany NY) (2015)

Bottom Line: The GMF-TG mice exhibited appearance phenotypes associated with premature aging.The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies.The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks.

View Article: PubMed Central - PubMed

Affiliation: Clinical Nutrition and Internal Medicine, Kobe Women's University, Kobe 654-8585, Japan.

ABSTRACT
Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

No MeSH data available.


Related in: MedlinePlus

The expression of p21/waf1 mRNA and protein in WT and GMF-TG mice(A) The expression of p21/waf1 mRNA increased in the kidneys of the GMF-TG mice at 10 weeks, compared with the WT mice. The data is shown as means ± S.E. (10w WT; n=3, 10w GMF-TG; n=4). *; P < 0.05 vs. 10w WT mice. (B) In the kidneys at 60 weeks, the expression of p21/waf1 mRNA in the GMF-TG mice was reduced significantly, compared to that of the WT mice at the same age. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). **; P < 0.01 vs. 60 w WT mice. (C) This figure shows the results from western blot analyses of the p21/waf1 protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. The data shown is representative data on the estimated ratios of p21/waf1 to α-actin, in the case of equivalent protein loading within a gel. Increased p21/waf1 protein levels were detected in the GMF-TG mice at 10 weeks, compared with the WT mice. However, there was no difference in the levels of p21/waf1 protein between the GMF-TG and WT mice at 60 weeks. The data is shown as means ± S.E. (10, 60w WT; n=3, 10, 60w GMF-TG; n=3). *; P < 0.05 vs. 10w WT mice. N.S.; not significant versus 60w WT mice.
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Figure 9: The expression of p21/waf1 mRNA and protein in WT and GMF-TG mice(A) The expression of p21/waf1 mRNA increased in the kidneys of the GMF-TG mice at 10 weeks, compared with the WT mice. The data is shown as means ± S.E. (10w WT; n=3, 10w GMF-TG; n=4). *; P < 0.05 vs. 10w WT mice. (B) In the kidneys at 60 weeks, the expression of p21/waf1 mRNA in the GMF-TG mice was reduced significantly, compared to that of the WT mice at the same age. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). **; P < 0.01 vs. 60 w WT mice. (C) This figure shows the results from western blot analyses of the p21/waf1 protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. The data shown is representative data on the estimated ratios of p21/waf1 to α-actin, in the case of equivalent protein loading within a gel. Increased p21/waf1 protein levels were detected in the GMF-TG mice at 10 weeks, compared with the WT mice. However, there was no difference in the levels of p21/waf1 protein between the GMF-TG and WT mice at 60 weeks. The data is shown as means ± S.E. (10, 60w WT; n=3, 10, 60w GMF-TG; n=3). *; P < 0.05 vs. 10w WT mice. N.S.; not significant versus 60w WT mice.

Mentions: We attempted to demonstrate the mechanisms of laminopathy-based premature aging in the GMF-TG mice. It has been suggested that premature aging in laminopathy model mice is linked to p53 pathway activation [32]. The activated p53 pathway induces cell/tissue senescence and eventually leads to accelerated aging [22, 23]. We examined whether the expression of p21/waf1 gene, a p53 downstream target gene, would increase in the kidneys of the GMF-TG mice at 10 and 60 weeks, and found that the expression of p21/waf1 mRNA and protein at 10 weeks increased significantly, compared with the wild-type mice (Figure 9A, C and Figure Supplemental 2). However, at 60 weeks, a significant decrease in the expression of p21/waf1 mRNA was demonstrated in the GMF-TG mice, compared with the wild-type mice at the same age (Figure 9B). There was no statistically significant difference between protein expression of p21/waf1 in the kidney of the GMF-TG and wild-type mice at 60 weeks (Figure 9C and Figure Supplemental 2). These results suggested that the p53 pathway was activated only at an earlier age in the GMF-TG mice, or that some compensative responses might be activated during a later stage in these mice.


Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

Imai R, Asai K, Hanai J, Takenaka M - Aging (Albany NY) (2015)

The expression of p21/waf1 mRNA and protein in WT and GMF-TG mice(A) The expression of p21/waf1 mRNA increased in the kidneys of the GMF-TG mice at 10 weeks, compared with the WT mice. The data is shown as means ± S.E. (10w WT; n=3, 10w GMF-TG; n=4). *; P < 0.05 vs. 10w WT mice. (B) In the kidneys at 60 weeks, the expression of p21/waf1 mRNA in the GMF-TG mice was reduced significantly, compared to that of the WT mice at the same age. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). **; P < 0.01 vs. 60 w WT mice. (C) This figure shows the results from western blot analyses of the p21/waf1 protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. The data shown is representative data on the estimated ratios of p21/waf1 to α-actin, in the case of equivalent protein loading within a gel. Increased p21/waf1 protein levels were detected in the GMF-TG mice at 10 weeks, compared with the WT mice. However, there was no difference in the levels of p21/waf1 protein between the GMF-TG and WT mice at 60 weeks. The data is shown as means ± S.E. (10, 60w WT; n=3, 10, 60w GMF-TG; n=3). *; P < 0.05 vs. 10w WT mice. N.S.; not significant versus 60w WT mice.
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Related In: Results  -  Collection

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Figure 9: The expression of p21/waf1 mRNA and protein in WT and GMF-TG mice(A) The expression of p21/waf1 mRNA increased in the kidneys of the GMF-TG mice at 10 weeks, compared with the WT mice. The data is shown as means ± S.E. (10w WT; n=3, 10w GMF-TG; n=4). *; P < 0.05 vs. 10w WT mice. (B) In the kidneys at 60 weeks, the expression of p21/waf1 mRNA in the GMF-TG mice was reduced significantly, compared to that of the WT mice at the same age. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). **; P < 0.01 vs. 60 w WT mice. (C) This figure shows the results from western blot analyses of the p21/waf1 protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. The data shown is representative data on the estimated ratios of p21/waf1 to α-actin, in the case of equivalent protein loading within a gel. Increased p21/waf1 protein levels were detected in the GMF-TG mice at 10 weeks, compared with the WT mice. However, there was no difference in the levels of p21/waf1 protein between the GMF-TG and WT mice at 60 weeks. The data is shown as means ± S.E. (10, 60w WT; n=3, 10, 60w GMF-TG; n=3). *; P < 0.05 vs. 10w WT mice. N.S.; not significant versus 60w WT mice.
Mentions: We attempted to demonstrate the mechanisms of laminopathy-based premature aging in the GMF-TG mice. It has been suggested that premature aging in laminopathy model mice is linked to p53 pathway activation [32]. The activated p53 pathway induces cell/tissue senescence and eventually leads to accelerated aging [22, 23]. We examined whether the expression of p21/waf1 gene, a p53 downstream target gene, would increase in the kidneys of the GMF-TG mice at 10 and 60 weeks, and found that the expression of p21/waf1 mRNA and protein at 10 weeks increased significantly, compared with the wild-type mice (Figure 9A, C and Figure Supplemental 2). However, at 60 weeks, a significant decrease in the expression of p21/waf1 mRNA was demonstrated in the GMF-TG mice, compared with the wild-type mice at the same age (Figure 9B). There was no statistically significant difference between protein expression of p21/waf1 in the kidney of the GMF-TG and wild-type mice at 60 weeks (Figure 9C and Figure Supplemental 2). These results suggested that the p53 pathway was activated only at an earlier age in the GMF-TG mice, or that some compensative responses might be activated during a later stage in these mice.

Bottom Line: The GMF-TG mice exhibited appearance phenotypes associated with premature aging.The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies.The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks.

View Article: PubMed Central - PubMed

Affiliation: Clinical Nutrition and Internal Medicine, Kobe Women's University, Kobe 654-8585, Japan.

ABSTRACT
Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

No MeSH data available.


Related in: MedlinePlus