Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells

Abstract

Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 3',5' monophosphate (cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter-3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.

Association of Indoxyl Sulfate with Heart Failure among Patients on Hemodialysis

“…The finding was independent of a series of conventional and unconventional risk factors, including age, sex, BMI, systolic BP, history of primary hypertension, history of coronary disease, history of diabetes, There has been a growing mass of evidence that IS is involved in the progression of CKD by inducing oxidative stress or other pathways. IS-induced reactive oxygen species production through a pathway involving NADPH oxidase or NADPHlike oxidase (20,21). In addition, IS strongly decreased the level of the nonenzymatic antioxidant glutathione in endothelial cells (22,23).…”

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

“…IS plays a role in inflammation-related processes by inducing production of reactive oxygen species in endothelial cells, 14,15 increasing endothelial microparticle release, 16 enhancing the proliferation of vascular smooth muscle cells, 17 and inhibiting endothelial cell repair. 18 IS increases cardiac fibrosis 19 and osteoblastic resistance to parathyroid hormone, 20 which might contribute to vascular calcification. Also, pCS was shown to have an immune stimulating effect caused by the increase of leukocyte free radical production.…”

“…After establishing baseline levels (0 minutes), measurements were repeated after 2,10,20,30,60,90, and 120 minutes of exposure to HBSS with or without LPS or uremic solute(s).…”

p-Cresyl Sulfate and Indoxyl Sulfate in Hemodialysis Patients

“…gov NCT00500682/NCT00501046]). Furthermore, in vitro and animal data suggest that indoxyl sulfate contributes to CKDassociated bone mineral disease (14,15).…”