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Abstract: SA-PO733

Podocyte-Specific Knockout of the Transcriptional Factor C/EBPα Aggravates Podocyte Senescence and Kidney Injury in Aging Mice

Session Information

  • Geriatric Nephrology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Geriatric Nephrology

  • 1100 Geriatric Nephrology

Authors

  • Zhang, Liwen, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Zhou, Fangfang, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Jian, Liu, Ruijin Hospital, Shanghai, China
  • Yu, Xialian, Ruijin Hospital Institute of kidney research, Shanghai, China
  • Liu, Yunzi, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Wang, Weiming, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Background

CCAAT/enhancer binding protein α (C/EBPα) is a widely expressed transcriptional factor, participating in regulation of metabolism, inflammation and differentiation. We have previously showed that C/EBPα expression was suppressed in glomerular cells, particularly in podocytes, in focal segmental glomerulosclerosis (FSGS), and have demonstrated its anti-inflammatory effects in FSGS in vivo and in vitro. And as terminally differentiated cells, podocytes are vulnerable to stress and play a central role in kidney aging. However, the specific role of C/EBPα in kidney aging remains undefined.

Methods

By crossing floxed C/EBPα mice with Pod-Cre mice, we generated podocyte-specific C/EBPα knockout mice. Both the homozygous transgenic mice (KO) and their wild-type littermates (WT) were sacrificed at 3 and 20 months of age as young and aging groups, respectively. Immortalized mouse podocyte line with transient C/EBPα overexpression and induced senescence by adriamycin (ADR) were used for in vitro experiments.

Results

KO-Young kidneys showed little morphological or gene expression change except reduced C/EBPα compared to WT-Young kidneys. In WT-Aging mice, foot process effacement, positive senescence-associated β-galactosidase (SA-β-Gal) staining accumulation in podocytes, glomerulosclerosis and tubular basement membrane thickening occurred, accompanied by epithelial-mesenchymal transdifferentiation and AMPK-SIRT1-PGC1α-mitochondria axis inhibition in tubular cells. These were aggravated in KO-Aging mice, as well as significant albuminuria and decreased podocyte markers occurred. In ADR induced senescent model in cultured podocytes, C/EBPα was down-regulated, and vimentin, CTGF, VEGFA and IL-6 increased. These phenotypes was rescued by C/EBPα overexpression.

Conclusion

These findings suggest that loss of C/EBPα accelerates podocyte senescence, aggravating glomerulosclerosis and tubular injury in aging mice. Targeting C/EBPα in podocytes may be a novel strategy for improving kidney aging.

Funding

  • Government Support - Non-U.S.