ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

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


The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2023 and some content may be unavailable. To unlock all content for 2023, please visit the archives.

Abstract: FR-PO1075

Lcn2 Plays a Key Role in Dot1l-HDAC2-ET1-Mediated Kidney Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Tsilosani, Akaki, Albany Medical Center, Albany, New York, United States
  • Gao, Chao, Albany Medical Center, Albany, New York, United States
  • Guo, Chenchun, Albany Medical Center, Albany, New York, United States
  • Chen, Enuo, Albany Medical Center, Albany, New York, United States
  • Zhang, Wenzheng, Albany Medical Center, Albany, New York, United States

Kidney fibrosis is a hallmark of chronic kidney disease. The genetic and epigenetic factors regulating kidney fibrosis are largely unknown. Kidney injury marker Lipocalin 2 (Lcn2) is involved in kidney fibrosis. We reported that Aqp2Cre mice express Cre specifically in Aqp2+ progenitor cells, which generates at least 5 types of cells forming distal convoluted tubule 2 (DCT2), connecting tubule (CNT) and collecting duct (CD). Our recent studies also indicated that disruption of histone H3 K79 methyltransferase Dot1l in Aqp2+ progenitor cells led to upregulation of endothelin 1 (ET1) and kidney fibrosis through histone deacetylase 2 (HDAC2) during normal aging. Here, we hypothesize that Lcn2 is a new component of this process and upregulates HDAC2, which in turn increases ET1 and facilitates kidney fibrosis.


Using the Aqp2Cre driver, we developed three conditional knockout mice: 1) DCT2/CNT/CD-specific Dot1l conditional knockout mice (Dot1f/f Aqp2Cre or Dot1lAC); 2) DCT2/CNT/CD-specific Dot1l and Edn1 double conditional knockout mice (Dot1lf/f Edn1f/f Aqp2Cre or DEAC); 3) DCT2/CNT/CD-specific Dot1l conditional knockout plus Lcn2 global knockout mice (Dot1f/f Aqp2Cre Lcn2-/- or DL-/-). WT and the three knockout mice were analyzed at the age of 14 months. A variety of approaches including immunofluorescence staining coupled by high-resolution confocal microscopy, metabolic assays, real-time RT-qPCR, and Western blotting were used to assess kidney fibrosis, kidney function, and/or expression of HDAC2, Lcn2, and ET1 in mice, in IMCD3 cells overexpressing Lcn2, or in IMCD3 cells treated with various doses of recombinant Lcn2.


Like DEAC vs. Dot1AC mice, DL-/- vs. Dot1AC mice displayed less pronounced kidney fibrosis and improved kidney function. While high Lcn2 expression remained in DEAC vs. Dot1AC mice, significantly reduced HDAC2 and ET1 levels were observed in DL-/- vs. Dot1AC. In IMCD3 cells, silencing Dot1l in IMCD3 cells led to upregulation of Lcn2, and addition of recombinant Lcn2 or overexpression of Lcn2 increased expression of HDAC2 and ET1.


Dot1l-Lcn2-HDAC2-ET1-kidney fibrosis may be considered as a new fibrogenesis pathway. That is, disruption of Dot1l in Aqp2+ progenitor cells not only directly upregulates ET1, but also indirectly through Lcn2, which positively regulates HDAC2, further facilitating ET1-mediated kidney fibrosis.


  • NIDDK Support