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.
Highlights
Chronic diseases, including cardiovascular disease, diabetes and cancer, account for a high rate of mortality [1], and aging is a notable risk factor for the progression of chronic diseases [2, 3]
It is known that glia maturation factor-β (GMF) is upregulated in the central nervous system in neurowww.impactaging.com degenerative diseases, such as Alzheimer's disease [12, 13], suggesting that GMF overexpression in brain tissue might play important roles in the pathogenesis of these neurodegenerative diseases [10,11,12,13]
These findings suggest that the induction of GMF in renal proximal tubular cells by proteinuria might play a key role in the pathogenesis of renal diseases by enhancing oxidative injuries [14]
Summary
Chronic diseases, including cardiovascular disease, diabetes and cancer, account for a high rate of mortality [1], and aging is a notable risk factor for the progression of chronic diseases [2, 3]. CKD is a significant risk factor for cardiovascular disease, as well as for the progression to end-stage renal disease [4]. Chronic proteinuria is a sign of CKD, it plays an important role in the progression of CKD [6]. It has been suggested that GMF overexpression in brain tissue might be implicated in the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis [10,11,12,13].
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