Abstract: SA-PO804
“Nephrogenic” Systemic Fibrosis Is Driven by C-C Chemokine Receptor 2-Dependent Myeloid- and Resident Tissue-Derived Fibrocyte Activation
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Wagner, Brent, Kidney Institute of New Mexico and the University of New Mexico Health Science Center, Albuquerque, New Mexico, United States
- Do, Catherine, South Texas Veterans Health Care System, San Antonio, Texas, United States
- Tan, Chunyan, University of Texas Health Science Center, San Antonio, Texas, United States
- Drel, Viktor, University of Texas Health Science Center, San Antonio, Texas, United States
- Lee, Doug Yoon, University of Texas Health Science Center, San Antonio, Texas, United States
- Gorin, Yves C., University of Texas Health Science Center, San Antonio, Texas, United States
Background
Gadolinium-based contrast agents are now associated with multiple conditions, including ‘nephrogenic’ systemic fibrosis/gadolinium-associated systemic fibrosis (NSF) and symptoms attributed to gadolinium retention. Bone marrow-derived fibrocytes and the monocyte chemoattractant protein 1 (MCP1) inflammatory pathway have been implicated as mediators. Mechanistic studies are scant. We established a mouse model of NSF.
Methods
Marrow was transplanted to lethally-irradiated mice: 1) recipients with 5/6 nephrectomies received green fluorescent protein- (GFP-) expressing marrow, 2) C-C chemokine receptor 2- (CCR2-) deficient mice received GFP-expressing marrow, and 3) wild-type mice received CCR2-deficient marrow. After engraftment periods, recipients were randomized to untreated or gadolinium-based contrast agent treatment (Omniscan—96% gadodiamide—2.5 mmol/kg, 20 doses intraperitoneally over 4 weeks).
Results
Dermal cellularity was increased in contrast-treated GFP chimeric mice. Compared to control, skin GFP, fibronectin, and type I collagen were increased in the contrast-treated chimeric animals. Importantly, CD45RO—a fibrocyte marker—was abundant in the dermis of contrast-treated animals and expressed by the myeloid cells. Many of these cells expressed cytoplasmic α-smooth muscle cell actin, a marker of myofibroblast activation. Activated myofibroblasts and fibrosis colocalized with the myeloid marker in contrast-treated animals. MCP-1 and CCR-2 were increased in the tissues from contrast-treated mice. CCR2-deficient recipients of GFP-expressing marrow had a partial abrogation of gadolinium-induced pathology and displayed less GFP positivity in the skin. Wild-type animals that received CCR2-deficient marrow had a complete abrogation of dermal pathology.
Conclusion
Systemic fibrosis is induced by gadolinium contrast in mice. The abundance of myeloid cells in an involved organ, the skin, in tandem with a fibrocyte marker—CD45RO—supports the blood-borne circulating fibrocyte hypothesis of the disease. This is the first demonstration of fibrocyte trafficking ever demonstrated in mice. Similar to what is observed in a rat model, our data demonstrate that the monocyte chemoattractant protein 1/CCR2 axis plays a critical role in the pathogenesis of gadolinium-induced systemic fibrosis.
Funding
- NIDDK Support