Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis
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Updated: May 14, 2026
Methods to Study Mrp4-containing Macromolecular Complexes in the Regulation of Fibroblast Migration
Published on: May 19, 2016
Valerie S LeBleu1, Yingqi Teng, Joyce T O'Connell
1Department of Medicine, Beth Israel Deaconess Medical Center, Division of Matrix Biology, Boston, Massachusetts, USA.
Abstract:
The functional contribution of myofibroblasts in fibrosis is not well understood. Using a new genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify HE4 (encoding human epididymis protein 4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most upregulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys and is elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4-neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively these studies suggest that HE4 is a potential biomarker of renal fibrosis and a new therapeutic target.
Insights
Researchers identified HE4 (human epididymis protein 4) as a key factor in kidney fibrosis. Targeting HE4 with antibodies reduced fibrosis, suggesting it
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- The role of myofibroblasts in fibrosis remains unclear.
- Understanding myofibroblast function is crucial for developing anti-fibrotic therapies.
Purpose of the Study:
- To identify key genes and molecular mechanisms driving fibrosis-associated myofibroblast activation.
- To investigate the therapeutic potential of targeting identified factors in kidney fibrosis.
Main Methods:
- Utilized a novel genetic mouse model for myofibroblast isolation and tracking.
- Performed gene expression profiling to identify upregulated genes in fibrotic conditions.
- Conducted biological validation, including protease activity assays and antibody-mediated neutralization studies.
- Evaluated therapeutic efficacy in three distinct mouse models of renal disease.
Main Results:
- Identified HE4 (human epididymis protein 4) as the most significantly upregulated gene in fibrosis-associated myofibroblasts.
- Demonstrated that HE4 acts as a serine protease inhibitor, suppressing collagen I degradation.
- Confirmed HE4 targets, including serine proteases Prss35 and Prss23, are functionally relevant in kidney fibrosis.
- Showed that HE4-neutralizing antibodies accelerated collagen I degradation and ameliorated fibrosis in mouse models.
Conclusions:
- HE4 is a critical mediator in kidney fibrosis, promoting myofibroblast-driven matrix deposition.
- HE4 represents a promising therapeutic target for renal fibrosis.
- HE4 may serve as a valuable biomarker for diagnosing and monitoring kidney fibrosis.
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