Transforming growth factor β-induced peritoneal fibrosis is mouse strain dependent.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis. The etiology is unclear, but genetic predisposition may be a contributing factor. We used adenovirus-mediated gene transfer of transforming growth factor (TGF) β1 to the peritoneum in four genetically distinct laboratory mouse strains to assess differences in fibrogenic response. METHODS: Mice from four genetic backgrounds (C57BL/6J, DBA/2J, C3H/HeJ and SJL/J) received an intraperitoneal injection of an adenovirus expressing TGFβ1 (AdTGFβ1) or control adenovirus (AdDL) and were assessed 4 and 10 days after infection. Submesothelial thickening, angiogenesis and gene expression were quantified from peritoneal tissue. Protein was extracted from omental tissue and assessed for collagen, E-cadherin and TGFβ signaling pathway proteins. RESULTS: There was a graded response among the mouse strains to the peritoneal overexpression of TGFβ1. TGFβ1 induced a significant fibrogenic response in the C57BL/6J mice, whereas the SJL/J mice were resistant. The DBA/2J and the C3H/HeJ mice had intermediate responses. A similar graded response was seen in collagen protein levels in the omental tissue and in fibrosis-associated gene expression. TGFβ type 1 receptor and SMAD signaling pathways appeared to be intact in all the mouse strains. CONCLUSIONS: There were significant differences in mouse strain susceptibility to peritoneal fibrosis, suggesting that genetic factors may play a role in the development of peritoneal fibrosis and possibly EPS. As early TGFβ1 signaling mechanisms appear to be intact, we hypothesize that fibrosis resistance in the SJL/J mice lies further down the wound-healing cascade or in an alternate, non-SMAD pathway. Nephrol Dial Transplant 2013 Aug; 28(8):2015-27

The role of mouse strain differences in the susceptibility to fibrosis: A systematic review

In humans, a number of genetic factors have been linked to the development of fibrosis in a variety of different organs. Seeking a wider understanding of this observation in man is ethically important. There is mounting evidence suggesting that inbred mouse strains with different genetic backgrounds demonstrate variable susceptibility to a fibrotic injury. We performed a systematic review of the literature describing strain and organ specific response to injury in order to determine whether genetic susceptibility plays a role in fibrogenesis. Data were collected from studies that were deemed eligible for analysis based on set inclusion criteria, and findings were assessed in relation to strain of mouse, type of injury and organ of investigation. A total of 44 studies were included covering 21 mouse strains and focusing on fibrosis in the lung, liver, kidney, intestine and heart. There is evidence that mouse strain differences influence susceptibility to fibrosis and this appears to be organ specific. For instance, C57BL/6J mice are resistant to hepatic, renal and cardiac fibrosis but susceptible to pulmonary and intestinal fibrosis. However, BALB/c mice are resistant to pulmonary fibrosis but susceptible to hepatic fibrosis. Few studies have assessed the effect of the same injury stimulus in different organ systems using the same strains of mouse. Such mouse strain studies may prove useful in elucidating the genetic as well as epigenetic factors in humans that could help determine why some people are more susceptible to the development of certain organ specific fibrosis than others