Launonen H [1], Luiskari L [1], Pang Z [1], Linden J [2] , Siltari A [1,3], Korpela R [1], Vapaatalo H [1]

Affiliates

1. Faculty of Medicine, Pharmacology, University of Helsinki, Finland 2. Faculty of Veterinary Medicine, Helsinki Institute of Life Science, University of Helsinki, Finland 3. Faculty of Medicine and Health Technology, Tampere University, Finland

Abstract

Background

Recently, we have shown evidence of the local production of aldosterone in the large intestine of mice. We also locally identified protein and mRNA of the terminal enzyme, CYP11B2, regulating aldosterone production. Such finding may have implications on sodium and water absorption as well as potassium excretion. A growing body of literature has shown evidence of the relationship between the locally produced aldosterone and inflammatory conditions. For instance, it has been reported that the increased local aldosterone production and inflammation in the kidney of diabetic rats can be attenuated using aldosterone synthase inhibitor FAD-286.

We used an experimental model of inflammatory bowel disease, DSS-induced inflammation, to evaluate the role of locally synthesized aldosterone and the possibility for its attenuation using FAD286 administration.

Materials and Methods

Sprague Dawley rats were induced acute colitis by administering 5 %(w/v) dextran sodium sulfate (DSS) 40 kDa into their drinking water for 1 week. They were treated using 30 mg/kg/day FAD286 injections during 12 days, starting 3 days prior to the beginning of colitis induction. Control groups were healthy mice and mice receiving DSS.

Following euthanasia, the severity of colonic inflammation was evaluated macroscopically and histologically. Local aldosterone production as well as the level of CYP11B2 were assessed by using Elisa and Western blot.

Results

DSS induced intestinal inflammation and FAD286 administration reduced the aldosterone concentration by half in the adrenal glands. Interestingly, the highest levels of local intestinal aldosterone levels were found from animals receiving FAD286 injections. A six kDa difference in molecular weight was observed, by Western blot, between the adrenal and colonic CYP11B2 enzyme, which may have affected the inhibitory effect of FAD286 in the colon. Intriguingly, FAD286 also decreased body weight and increased intestinal bleeding compared with DSS group. Also, FAD286 aggravated signs of inflammation macroscopically and histologically.

Conclusions

FAD286 suppressing the adrenal production of aldosterone showed harmful effects on intestinal inflammation. Local intestinal aldosterone production does not play a crucial role in the development of DSS -induced intestinal inflammation.