ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO484

Plant Homeodomain (PHD) Finger Protein 14 (PHF14) Inhibits Renal Fibrosis via Repressing Connective Tissue Growth Factor Induced by Hypoxia-Inducible Factor 1 Alpha

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Chen, Sixiu, Division of Nephrology, Kidney Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China
  • Huang, Linxi, Division of Nephrology, Kidney Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China
  • Mao, Zhiguo, Division of Nephrology, Kidney Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China
Background

Renal fibrosis is the final common pathological manifestation of chronic kidney diseases progressing to ESRD, while no effective way has been found to reverse it. Chronic hypoxia was thought to play an important role in renal fibrosis. PHF14, a novel histone binding protein, was discovered in our previous studies to be an innate inhibitor of renal fibrosis. However, the mechanism of PHF14 is not unraveled. We hypothesized PHF14 may be induced by hypoxia-inducible factor 1 α (HIF-1α), and repress the over-expression of connective tissue growth factor (CTGF) by regulating histone methylation.

Methods

We confirmed the biological function of PHF14 in PHF14 conditional knockout mice following aristolochic acid administration. Relationship between hypoxia and PHF14 has been explored in NRK52E cells. We detected the interactions of PHF14 with H3K4me3 and H3K27me3 using Chromatin Immunoprecipitation (ChIP) and Co-immunoprecipitation (Co-IP). We also generated PHF14-KO cell via CRISPR/Cas9 system.

Results

1. Compared with controls, PHF14 conditional knockout mice presented aggravated renal fibrosis and worse renal function (Figure 1A-1C). 2. PHF14 was induced in hypoxia environment in vitro. And PHF14 was upregulated by HIF-1α stimulant DMOG and repressed by HIF-1α inhibitor KC7F2 (Figure 1D). ChIP detected HIF-1α binding on the promoter of PHF14 and CTGF. 3. PHF14 knockdown enhanced CTGF expression following DMOG stimulation in vitro and PHF14 could bind on the promoter of CTGF, which was proved by ChIP. 4. The enrichment of histone methylation in CTGF promoter induced by HIF-1 α was changed in PHF14-KO cells. Co-IP validated PHF14 could interact with H3K4me3 and H3K27me3.

Conclusion

Lack of PHF14 deteriorated aristolochic acid nephropathy in mice. PHF14, which was induced by HIF-1α, inhibited CTGF expression via regulating histone methylation in CTGF promoter.

Figure 1

Funding

  • Government Support - Non-U.S.