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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 serum creatinine levels in WT and GMF-TG miceThis figure shows the result of the serum creatinine levels in the WT and GMF-TG mice, which revealed that serum creatinine was increased in the GMF-TG mice, compared with the WT mice. The data is shown as means ± S.E. (WT; n=4, average age; 84.8 ± 0.25 weeks, GMF-TG; n=4 average age; 72.8 ± 6.24 weeks). *; P < 0.05 vs. WT mice.
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Figure 8: The serum creatinine levels in WT and GMF-TG miceThis figure shows the result of the serum creatinine levels in the WT and GMF-TG mice, which revealed that serum creatinine was increased in the GMF-TG mice, compared with the WT mice. The data is shown as means ± S.E. (WT; n=4, average age; 84.8 ± 0.25 weeks, GMF-TG; n=4 average age; 72.8 ± 6.24 weeks). *; P < 0.05 vs. WT mice.

Mentions: The connective tissue growing factor (CTGF) gene is known as a downstream mediator of TGF-β1. In order to investigate age-associated changes in the kidneys, we evaluated the expression levels of the TGF-β1 and CTGF genes by real-time PCR analyses. In the kidney tissue of the GMF-TG mice at 10 weeks, the expression of TGF-β1 mRNA increased significantly, compared with the wild-type mice (Figure 7A). However, there was no statistically significant difference between the expression of CTGF mRNA of the kidney of the GMF-TG and wild-type mice at 10 weeks (Figure 7B). Importantly, in the GMF-TG mice at 60 weeks, the expression of both TGF-β1 and CTGF mRNA in the kidney increased significantly, compared with that of the wild-type mice (Figure 7C and D). It has been reported that serum creatinine was increased in old mice compared with young mice, suggesting the decline of renal function with advancing age [31]. Figure 8 showed that serum creatinine was increased in the old GMF-TG mice (Average age: 72.8 weeks) compared with the old wild-type mice (Average age: 84.8 weeks). These results demonstrated that the GMF-TG mice showed premature-aging phenotypes in the kidney tissue, probably through an accumulation of prelamin A. These findings suggested that the GMF-TG mice might show a tendency for laminopathy-based premature aging.


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 serum creatinine levels in WT and GMF-TG miceThis figure shows the result of the serum creatinine levels in the WT and GMF-TG mice, which revealed that serum creatinine was increased in the GMF-TG mice, compared with the WT mice. The data is shown as means ± S.E. (WT; n=4, average age; 84.8 ± 0.25 weeks, GMF-TG; n=4 average age; 72.8 ± 6.24 weeks). *; P < 0.05 vs. WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543038&req=5

Figure 8: The serum creatinine levels in WT and GMF-TG miceThis figure shows the result of the serum creatinine levels in the WT and GMF-TG mice, which revealed that serum creatinine was increased in the GMF-TG mice, compared with the WT mice. The data is shown as means ± S.E. (WT; n=4, average age; 84.8 ± 0.25 weeks, GMF-TG; n=4 average age; 72.8 ± 6.24 weeks). *; P < 0.05 vs. WT mice.
Mentions: The connective tissue growing factor (CTGF) gene is known as a downstream mediator of TGF-β1. In order to investigate age-associated changes in the kidneys, we evaluated the expression levels of the TGF-β1 and CTGF genes by real-time PCR analyses. In the kidney tissue of the GMF-TG mice at 10 weeks, the expression of TGF-β1 mRNA increased significantly, compared with the wild-type mice (Figure 7A). However, there was no statistically significant difference between the expression of CTGF mRNA of the kidney of the GMF-TG and wild-type mice at 10 weeks (Figure 7B). Importantly, in the GMF-TG mice at 60 weeks, the expression of both TGF-β1 and CTGF mRNA in the kidney increased significantly, compared with that of the wild-type mice (Figure 7C and D). It has been reported that serum creatinine was increased in old mice compared with young mice, suggesting the decline of renal function with advancing age [31]. Figure 8 showed that serum creatinine was increased in the old GMF-TG mice (Average age: 72.8 weeks) compared with the old wild-type mice (Average age: 84.8 weeks). These results demonstrated that the GMF-TG mice showed premature-aging phenotypes in the kidney tissue, probably through an accumulation of prelamin A. These findings suggested that the GMF-TG mice might show a tendency for laminopathy-based premature aging.

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