Research Project
10477162
Chronic kidney disease (CKD) remains a significant cause of morbidity and mortality, and therapies are limited. One exciting new avenue for therapy is targeting the gut microbes, as there appear to be several gut microbe-derived toxins that are increased in CKD. Unfortunately, non-specific attempts to manipulate the gut microbe, using prebiotics or probiotics for example, has not been effective2,3. A logical alternative approach, however, would be to identify and specifically target the key microbial pathways involved. One potentially toxic metabolite is trimethylamine N-oxide (TMAO). TMAO is generated from trimethylamine, which is in turn generated by gut microbes, via the enzyme CutC4. TMAO is increased in CKD patients5-14, it promotes renal fibrosis in mice10,16, and lowering TMAO has beneficial effects16-18. However, the mechanisms by which TMAO exerts its negative effects are unclear, and therapies to safely lower CutC have yet to be established. In our recently published work, we identified the first, and thus far only, receptor for TMAO: the stress kinase PERK19. PERK promotes inflammation and apoptosis, raising the possibility that it may mediate the effects of TMAO on the kidney. In our new unpublished work, we performed a drug repurposing screen to identify inhibitors of CutC. We identified a new drug, Drug X, which inhibits CutC in vitro, and lowers TMAO in vivo. Importantly, Drug X is already known to be safe in humans. We hypothesize that TMAO promotes CKD via PERK. Our aims are to determine (1) the effects of TMAO on renal PERK, gene expression, and fibrosis; (2) whether the effects of TMAO are dependent upon PERK; and (3) whether specifically lowering TMA production with Drug X can reduce PERK activity and renal fibrosis in mouse CKD models. Our team is uniquely poised for these studies, as it includes Sudha Biddinger, with expertise in the TMAO pathway19-21; Emily Balskus, with expertise in gut microbial chemistry4,15,22-24; and David Salant25-28 and Agnes Fogo29-31, experts in renal disease and pathology. We expect that our studies will (1) reveal PERK to be a key mediator of TMAO effects on renal fibrosis; and (2) show CutC inhibition with Drug X can reduce CKD in mice. Thus, these studies may provide Drug X as a new tool for manipulating the gut microbiome in humans for the treatment of CKD.
