Sandra Sexton1, Ryan Tulowitzki2, Craig A Jones1, Silvi Shah2, George Hajduczok2, Kenneth W Gross1, Mandip Panesar3. 1. Roswell Park Cancer Institute, Buffalo, NY, USA. 2. Erie County Medical Center, State University of New York at Buffalo, 462 Grider Street, Buffalo, NY, 14215, USA. 3. Erie County Medical Center, State University of New York at Buffalo, 462 Grider Street, Buffalo, NY, 14215, USA. mpanesar@ecmc.edu.
Abstract
BACKGROUND: Renin-angiotensin system (RAS) activation increases angiotensin II production stimulating profibrotic factors, especially in the setting of chronic kidney disease. Nephrogenic systemic fibrosis (NSF) has been associated with gadolinium (Gd) exposure and renal failure. RAS involvement in NSF is unclear compared to transforming growth factor beta and Smad. RenTag mice were chosen to investigate the role of RAS in NSF-like dermal fibrosis because they demonstrated dermal fibrosis at birth, perturbations of RAS in subcutaneous tissue, and renal failure within 4 weeks of age. METHODS: Wild-type and RenTag mice were injected weekly with a supratherapeutic dose of intravenous gadodiamide (3.0 mmol/kg body weight) and killed at 12 weeks of age for skin and kidney histology. RESULTS: RenTag mice had elevated BUN levels, pitted kidneys, and glomerular damage. RenTag mice skin revealed an increased density of fibroblasts, no mucopolysaccharide deposits, and increased collagen fibril density regardless of Gd exposure. Skin and kidney histopathology of wild-type mice were normal regardless of Gd exposure. CD34 positivity was higher in RenTag compared to wild-type. CONCLUSIONS: Since RenTag dermal lesions remained unchanged after gadolinium exposure in the setting of renal failure, this animal model suggests perturbations of subcutaneous RAS may be involved in Gd-naïve dermal fibrosis.
BACKGROUND: Renin-angiotensin system (RAS) activation increases angiotensin II production stimulating profibrotic factors, especially in the setting of chronic kidney disease. Nephrogenic systemic fibrosis (NSF) has been associated with gadolinium (Gd) exposure and renal failure. RAS involvement in NSF is unclear compared to transforming growth factor beta and Smad. RenTag mice were chosen to investigate the role of RAS in NSF-like dermal fibrosis because they demonstrated dermal fibrosis at birth, perturbations of RAS in subcutaneous tissue, and renal failure within 4 weeks of age. METHODS: Wild-type and RenTag mice were injected weekly with a supratherapeutic dose of intravenous gadodiamide (3.0 mmol/kg body weight) and killed at 12 weeks of age for skin and kidney histology. RESULTS: RenTag mice had elevated BUN levels, pitted kidneys, and glomerular damage. RenTag mice skin revealed an increased density of fibroblasts, no mucopolysaccharide deposits, and increased collagen fibril density regardless of Gd exposure. Skin and kidney histopathology of wild-type mice were normal regardless of Gd exposure. CD34 positivity was higher in RenTag compared to wild-type. CONCLUSIONS: Since RenTag dermal lesions remained unchanged after gadolinium exposure in the setting of renal failure, this animal model suggests perturbations of subcutaneous RAS may be involved in Gd-naïve dermal fibrosis.
Authors: Philip Kam-Tao Li; Chi Bon Leung; Kai Ming Chow; Yuk Lun Cheng; Samuel Ka-Shun Fung; Siu Ka Mak; Anthony Wing-Chung Tang; Teresa Yuk-Hwa Wong; Chun Yu Yung; Jonathan Chee-Unn Yung; Alex Wai-Yin Yu; Cheuk Chun Szeto Journal: Am J Kidney Dis Date: 2006-05 Impact factor: 8.860
Authors: C D Sigmund; K Okuyama; J Ingelfinger; C A Jones; J J Mullins; C Kane; U Kim; C Z Wu; L Kenny; Y Rustum Journal: J Biol Chem Date: 1990-11-15 Impact factor: 5.157