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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

Western blot of lamin A/C and the expression of Zmpste24 in WT and GMF-TG mice(A-B) These figures show the results from western blot analyses of the lamin A/C protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. Prelamin A was absent in the WT mice at 10 and 60 weeks (A-B; Left) and the GMF-TG mice at 10 weeks (A; Right), but it was detectable in the GMF-TG mice at 60 weeks (B; Right). There were no significant differences between the lamin C protein levels in the WT and GMF-TG mice, confirming equal loading. (C) The expression of Zmpste24 mRNA tended to decrease 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=3). P < 0.09 vs. 10w WT mice. (D) The expression of Zmpste24 mRNA decreased in the kidneys of the GMF-TG mice at 60 weeks, compared with the WT mice. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). *; P < 0.01 vs. 60w WT mice.
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Figure 6: Western blot of lamin A/C and the expression of Zmpste24 in WT and GMF-TG mice(A-B) These figures show the results from western blot analyses of the lamin A/C protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. Prelamin A was absent in the WT mice at 10 and 60 weeks (A-B; Left) and the GMF-TG mice at 10 weeks (A; Right), but it was detectable in the GMF-TG mice at 60 weeks (B; Right). There were no significant differences between the lamin C protein levels in the WT and GMF-TG mice, confirming equal loading. (C) The expression of Zmpste24 mRNA tended to decrease 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=3). P < 0.09 vs. 10w WT mice. (D) The expression of Zmpste24 mRNA decreased in the kidneys of the GMF-TG mice at 60 weeks, compared with the WT mice. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). *; P < 0.01 vs. 60w WT mice.

Mentions: HGPS is associated with premature alopecia, which is one of the well-known premature-aging syndromes due to laminopathies, seen in humans [29]. Cells and tissue from HGPS patients exhibited an accumulation of abnormal lamin A (progerin) [17, 18]. The phenotypes characterized in the skin of the GMF-TG mice, such as alopecia and skin atrophy, seemed to be similar to that of laminopathy-based premature aging. Therefore, we hypothesized that an accumulation of abnormal lamin A resulted in the accelerated aging phenotypes shown in the GMF-TG mice. In order to analyze the abnormalities of the lamin A in the tissue of the GMF-TG mice, we first examined the lamin A protein in the kidney by western blotting, because GMF over-expression was ectopically induced in kidney tissue by proteinuria [7, 8]. At 10 weeks, no lamin A abnormalities were exhibited in the kidney of either the GMF-TG or wild-type mice (Figure 6A and Figure Supplemental 1A). However, at 60 weeks, an accumulation of abnormal lamin A (prelamin A) was detected in the kidneys of the GMF-TG mice, but not in the wild-type mice (Figure 6B and Figure Supplemental 1B). Next, we evaluated the expression levels of the cleaving enzyme of prelamin A (Zmpste24) gene in the kidneys by real-time PCR analyses to confirm the mechanism of the accumulated prelamin A. At 10 weeks, the expression of Zmpste24 mRNA tended to decrease in the GMF-TG mice (Figure 6C). At 60 weeks, a significant decrease was demonstrated in the expression of Zmpste24 mRNA in the GMF-TG mice, compared with the wild-type mice at the same age (Figure 6D). These results demonstrated that the GMF-TG mice exhibited an accumulation of prelamin A, accompanied by a reduction of Zmpste24 gene expression in the kidney tissue. On the basis of these results, we investigated the degree of aging in kidney tissue of the GMF-TG mice. In the kidney, aging-associated changes are characterized by structural changes, including glomerulosclerosis and interstitial fibrosis [30, 31], as well as the decline of renal function [31]. It has been suggested that the transforming growth factor-β1 (TGF-β1) gene is one of the factors that promote the process of renal interstitial fibrosis associ ated with aging [30].


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)

Western blot of lamin A/C and the expression of Zmpste24 in WT and GMF-TG mice(A-B) These figures show the results from western blot analyses of the lamin A/C protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. Prelamin A was absent in the WT mice at 10 and 60 weeks (A-B; Left) and the GMF-TG mice at 10 weeks (A; Right), but it was detectable in the GMF-TG mice at 60 weeks (B; Right). There were no significant differences between the lamin C protein levels in the WT and GMF-TG mice, confirming equal loading. (C) The expression of Zmpste24 mRNA tended to decrease 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=3). P < 0.09 vs. 10w WT mice. (D) The expression of Zmpste24 mRNA decreased in the kidneys of the GMF-TG mice at 60 weeks, compared with the WT mice. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). *; P < 0.01 vs. 60w WT mice.
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Figure 6: Western blot of lamin A/C and the expression of Zmpste24 in WT and GMF-TG mice(A-B) These figures show the results from western blot analyses of the lamin A/C protein in the kidney of the WT and GMF-TG mice at 10 and 60 weeks. Prelamin A was absent in the WT mice at 10 and 60 weeks (A-B; Left) and the GMF-TG mice at 10 weeks (A; Right), but it was detectable in the GMF-TG mice at 60 weeks (B; Right). There were no significant differences between the lamin C protein levels in the WT and GMF-TG mice, confirming equal loading. (C) The expression of Zmpste24 mRNA tended to decrease 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=3). P < 0.09 vs. 10w WT mice. (D) The expression of Zmpste24 mRNA decreased in the kidneys of the GMF-TG mice at 60 weeks, compared with the WT mice. The data is shown as means ± S.E. (60w WT; n=4, 60w GMF-TG; n=4). *; P < 0.01 vs. 60w WT mice.
Mentions: HGPS is associated with premature alopecia, which is one of the well-known premature-aging syndromes due to laminopathies, seen in humans [29]. Cells and tissue from HGPS patients exhibited an accumulation of abnormal lamin A (progerin) [17, 18]. The phenotypes characterized in the skin of the GMF-TG mice, such as alopecia and skin atrophy, seemed to be similar to that of laminopathy-based premature aging. Therefore, we hypothesized that an accumulation of abnormal lamin A resulted in the accelerated aging phenotypes shown in the GMF-TG mice. In order to analyze the abnormalities of the lamin A in the tissue of the GMF-TG mice, we first examined the lamin A protein in the kidney by western blotting, because GMF over-expression was ectopically induced in kidney tissue by proteinuria [7, 8]. At 10 weeks, no lamin A abnormalities were exhibited in the kidney of either the GMF-TG or wild-type mice (Figure 6A and Figure Supplemental 1A). However, at 60 weeks, an accumulation of abnormal lamin A (prelamin A) was detected in the kidneys of the GMF-TG mice, but not in the wild-type mice (Figure 6B and Figure Supplemental 1B). Next, we evaluated the expression levels of the cleaving enzyme of prelamin A (Zmpste24) gene in the kidneys by real-time PCR analyses to confirm the mechanism of the accumulated prelamin A. At 10 weeks, the expression of Zmpste24 mRNA tended to decrease in the GMF-TG mice (Figure 6C). At 60 weeks, a significant decrease was demonstrated in the expression of Zmpste24 mRNA in the GMF-TG mice, compared with the wild-type mice at the same age (Figure 6D). These results demonstrated that the GMF-TG mice exhibited an accumulation of prelamin A, accompanied by a reduction of Zmpste24 gene expression in the kidney tissue. On the basis of these results, we investigated the degree of aging in kidney tissue of the GMF-TG mice. In the kidney, aging-associated changes are characterized by structural changes, including glomerulosclerosis and interstitial fibrosis [30, 31], as well as the decline of renal function [31]. It has been suggested that the transforming growth factor-β1 (TGF-β1) gene is one of the factors that promote the process of renal interstitial fibrosis associ ated with aging [30].

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