Gut-derived uremic toxin indoxyl sulfate and aryl hydrocarbon receptor in renal osteodystrophy

Chronic kidney disease (CKD) affects 14% individuals worldwide. Changes in bone and mineral metabolism in CKD are ubiquitous (CKD- Mineral and Bone Disorder) including renal osteodystrophy with a fracture incidence of up to 5 times greater than the general population. While PTH lowering is the mainstay of therapy for decades this has not reduced fractures in patients or improve bone mechanics in pre-clinical models. This suggests additional factors involved in the pathogenesis of renal osteodystrophy such as uremic toxins due to either increased production or decreased renal excretion. One group of toxins are metabolized by intestinal microbiota from tryptophan and include indoxyl sulfate, a potent ligand for the aryl hydrocarbon receptor (AhR) with downstream effect in many signaling pathways important in bone remodeling and metabolism. In AhR-/- mice, there is impaired fracture healing and mineralization by microCT, and we have shown in vitro that indoxyl sulfate activates AhR canonical signaling in osteocytes. This activation decreased osteocyte mineralization and alkaline phosphatase activity that were reversed by AhR receptor blocker. In early osteocytes, indoxyl sulfate also suppressed the RANKL/OPG ratio (receptor activator of nuclear factor kappa-Β ligand/osteoprotegrin), and increased Wnt inhibitor expression, changes that were reversed or blunted with AhR inhibitor and would reduce overall bone remodeling. Further, in a rat model of progressive CKD, we demonstrated that the dietary fiber inulin reduced indoxyl sulfate levels and improves renal osteodystrophy. These data suggest that the gut-derived uremic toxin indoxyl sulfate activates the AhR and adversely affects bone in CKD.