C/EBP\u03b1 deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice

Liwen Zhang,Qingyang Ma,Xialian Yu,Ying Zhou,Yuchao Zhang,Yunzi Liu,Nan Chen,Yufei Zhu,Fangfang Zhou,Jian Liu,Weiming Wang

doi:10.1038/s41419-019-1933-2

Abstract

Kidney aging leads to an increased incidence of end-stage renal disease (ESRD) in the elderly, and aging is a complex biological process controlled by signaling pathways and transcription factors. Podocyte senescence plays a central role in injury resulting from kidney aging. Here, we demonstrated the critical role of C/EBPα in podocyte senescence and kidney aging by generating a genetically modified mouse model of chronological aging in which C/EBPα was selectively deleted in podocytes and by overexpressing C/EBPα in cultured podocytes, in which premature senescence was induced by treatment with adriamycin. Moreover, we illuminated the mechanisms by which podocyte senescence causes tubular impairment by stimulating HK-2 cells with bovine serum albumin (BSA) and chloroquine. Our findings suggest that C/EBPα knockout in podocytes aggravates podocyte senescence through the AMPK/mTOR pathway, leading to glomerulosclerosis, and that subsequent albuminuria exacerbates the epithelial–mesenchymal transdifferentiation of senescent tubular cells by suppressing autophagy. These observations highlight the importance of C/EBPα as a new potential target in kidney aging.

Highlights

As the global population has aged, the incidence of kidney disease in the expanding geriatric population has grown proportionally
By examining the colocalization of C/EBPα and the podocyte marker synaptopodin by immunofluorescence, we found that C/EBPα in the kidneys was mainly expressed in podocytes and that C/EBPα expression in podocytes was deleted in KO mice and downregulated upon aging (Fig. 1c)
ADR, a chemotherapeutic agent that causes DNA damage, was employed at a concentration of 0.5 μM to induce the premature senescence[10,11] of podocytes, and we found that the expression level of C/EBPα decreased significantly in podocytes treated with ADR (0.5 μM ADR group) compared with podocytes not treated with ADR (Fig. 7a, b)

Summary

Introduction

As the global population has aged, the incidence of kidney disease in the expanding geriatric population has grown proportionally. A progressive decline in the physiological function of all organs and systems is a common characteristic of aging[1] In the kidneys, this decline appears to involve an ~10% decrease in the glomerular filtration rate per decade after the age of 352. Aging induces the CAAT enhancer-binding proteins (C/EBPs) are a family of transcription factors belonging to the basic region leucine zipper (bZIP) family of proteins. They are widely expressed in liver, fat, and hematopoietic cells and other terminally differentiated cells[3]. The effects of C/EBPα in podocyte senescence and kidney aging remain unknown

Methods

Results

Conclusion