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


The Latest on Twitter

Kidney Week

Abstract: TH-OR117

Enzymatic Inactive Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Antibody-Mediated Podocyte Injury

Session Information

  • Mostly IgA Nephropathy
    November 07, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
    Abstract Time: 06:18 PM - 06:30 PM

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation


  • Reichelt, Julia, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Pohl, Sandra, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Zahner, Gunther, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Meyer-Schwesinger, Catherine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Group or Team Name

  • AG Meyer-Schwesinger

Membranous nephropathy (MN) is an autoimmune disease of the glomerulus characterized by upregulation of the ubiquitin proteasome system (UPS) in podocytes. Thereby, ubiquitin C-terminal hydrolase L1 (UCH-L1) is among the highest upregulated UPS enzymes and de novoexpressed in injured podocytes. Preliminary work demonstrates that proteasomal impairment and altered proteostasis depends on the enzymatic activity of UCH-L1 in naïve podocytes. We hypothesize that in MN oxidative-modification of UCH-L1 (secondary to oxidative stress) leads to the formation of a dysfunctional UCH-L1 enzyme, which perpetuates podocyte injury. Aim of this study is to understand the underlying mechanism for toxic loss of function of UCH-L1 in antibody-mediated podocyte injury.


In vivo experiments were performed by using unique mouse models with podocyte-specific overexpression of active UCH-L1 wildtype protein or inactive UCH-L1 I93M mutant protein (comparable to oxidative-modified UCH-L1). Mice were treated with anti-podocyte nephritis (APN) antibodies, sacrificed after 14 days, and analyzed by WB, enzyme activity assays, IHC and ELISA for proteinuria. For mechanistic studies, flag-tagged wildtype or mutant I93M UCH-L1 were cloned and transiently overexpressed in HEK-293T cells and used for proteasome interaction studies.


Mice overexpressing dysfunctional UCH-L1 I93M protein exhibited an accelerated disease course with an increased accumulation of polyubiquitinated proteins accompanied by elevated expression of proteasomal and lysosomal proteins in isolated glomeruli. We also observed reduced levels of slit membrane proteins such as nephrin and α-actinin-4 correlating with podocyte loss. Contrastingly, mice overexpressing active wildtype UCH-L1 in podocytes exhibited milder proteinuria and stable expression of podocyte-specific proteins in response to anti-podocyte antibodies after 14 days. In vitroimmunoprecipitation experiments demonstrated an interaction of wildtype UCH-L1 and UCH-L1 I93M with the proteasome, however only binding of UCH-L1 I93M decreased proteasomal activity.


These results strengthen the hypothesis that during MN a shift of UCH-L1 enzymatic activity to a dysfunctional protein negatively influences podocyte protein homeostasis by aberrant interactions with the proteasome.