Effects of CREG1 on Age-Associated Metabolic Phenotypes and Renal Senescence in Mice.

Yuki Endo,Jun Ueda,Michihiro Hashimoto,Ayumi Goto,Masataka Sugimoto,Hitoshi Yamashita

doi:10.3390/ijms22031276

Abstract

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction.

Highlights

Accepted: 26 January 2021Cellular repressor of E1A-stimulated genes 1 (CREG1), which is a secreted glycoprotein containing 220 amino acids, inhibits cell growth and enhances the differentiation of human embryonic teratocarcinoma NTERA-2 cells [1,2]
The loss of CREG1 leads to early embryonic death, as it is essential for early myocardial development, and CREG1 heterozygous mice are susceptible to diet-induced obesity (DIO)
Regarding the role of CREG1 in Brown adipose tissue (BAT) thermogenesis, we recently reported that CREG1 is able to stimulate brown adipogenesis and uncoupling protein 1 (UCP1) expression in vitro [21]

Summary

Introduction

Cellular repressor of E1A-stimulated genes 1 (CREG1), which is a secreted glycoprotein containing 220 amino acids, inhibits cell growth and enhances the differentiation of human embryonic teratocarcinoma NTERA-2 cells [1,2]. CREG1 binds the tumor suppressor pRb in vitro [1] and enhances p16INK4a -induced senescence by the transcriptional repression of cell cycle-regulated genes, such as cyclin A and cyclin B, in immortal LiFraumeni Syndrome fibroblasts, and osteosarcoma and fibrosarcoma cell lines [3]. These studies suggest a potential role of CREG1 in age-associated disorders in vivo. Similar to the p19ARF (p14ARF in human)/p53 pathway, the p16INK4a /Rb pathway is a major tumor suppressor pathway and plays critical roles in the induction and maintenance of cell cycle arrest during cellular senescence [7,8]. Studies using the genetic elimination of senescent cells have made great

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