Involvement of the renin–angiotensin system in the development of nephrogenic systemic fibrosis-like lesions in the RenTag mouse model

Abstract

Background Renin-angiotensin system (RAS) activation increases angiotensin II production which stimulates profibrotic factors especially in the setting of chronic kidney disease. Nephrogenic systemic fibrosis (NSF) is 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 intravenous gadodiamide (3.0mmol/kg body weight) and sacrificed 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’s 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.