Abstract: SA-OR23
The Role of D-dopachrome Tautomerase (Macrophage Migration Inhibitory Factor 2) in Kidney Fibrosis
Session Information
- CKD: New Insights into Mechanisms and Treatment Strategies
October 26, 2024 | Location: Room 24, Convention Center
Abstract Time: 05:10 PM - 05:20 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Herkens, Lea, Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Droste, Patrick, Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Karyniotakis, Konstantinos, Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Boor, Peter, Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Djudjaj, Sonja, Institute of Pathology, RWTH Aachen University, Aachen, Germany
Group or Team Name
- Laboratory of Nephropathology.
Background
The progression of most kidney diseases leads to kidney fibrosis. Numerous factors were shown to be involved in driving fibrosis, less is known about endogenous factors limiting fibrosis. One such protective factor is macrophage migration inhibitory factor (MIF), which was found to limit kidney fibrosis by abrogating the cell cycle arrest of tubular cells. Macrophage migration inhibitory factor-2 (MIF-2), also known as D-dopachrome tautomerase (D-DT), is a structural and functional homolog of MIF. Very little is known about the location, expression, and functional role of D-DT in kidney fibrosis.
Methods
The expression of D-DT in kidney fibrosis was analyzed in different animal models, i.e., unilateral ureteral obstruction (UUO), ischemia-reperfusion (IR), and patients’ biopsies using immunohistochemistry, immunofluorescence, rt-PCR, RNA in situ hybridization, Western blot and enzyme-linked immunosorbent assay (ELISA). Publicly available datasets and arrays were also re-analyzed and complemented by in vitro studies using human embryonic kidney (HEK) 293T cells. The functional role of D-DT in vivo was analyzed in D-DT knockout (KO) mice compared to wildtype littermates (WT) and by administration of recombinant D-DT in WT mice with UUO.
Results
D-DT mRNA and protein expression were mainly located in proximal tubules in both healthy murine and human kidneys. Its expression was significantly reduced in fibrosis in patients and animals with UUO and IR. Re-analysis of Ddt/DDT expression in murine and human publicly available array data further confirmed these findings. In vitro, HEK293T cells showed significantly decreased D-DT expression when challenged with the profibrotic transforming growth factor-β1 (TGF-β1). In vivo, compared to WT, D-DT KO mice developed significantly aggravated fibrosis in the UUO model while treatment with recombinant D-DT significantly improved fibrosis.
Conclusion
The data suggested that D-DT is mainly expressed in the proximal tubules in both mice and men and similarly decreased in fibrosis in both species. In vivo experiments suggested a protective role of D-DT in kidney fibrosis, similar to MIF; adding a new endogenous fibrosis-limiting factor. Future work will focus on potential mechanisms of the renoprotective effects of D-DT.
Funding
- Government Support – Non-U.S.