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

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.

Role for "uremic toxin" in the progressive loss of intact nephrons in chronic renal failure.

We studied the effect on the progression of glomerular sclerosis of two different experimental maneuvers, peritoneal dialysis and oral adsorbent, which remove circulating substances in different fashions. Munich-Wistar rats with established glomerular sclerosis, verified by renal biopsy analysis at seven weeks after subtotal nephrectomy, were treated for four weeks with either peritoneal dialysis (PD) or oral charcoal adsorbent (AST-120). Treatment was initiated at eight weeks. Rats were paired in treatment and control groups according to the similarity in the degree of sclerosis determined at biopsy with a minimum of 50 glomeruli analyzed. Systolic blood pressure and BUN and creatinine clearance, measured at seven to eight weeks, were not different among groups. In Group 2 rats, PD was performed with 1.5% dextrose for eight one-hour cycles, six days per week, while Group 1 control rats had zero indwelling time of the dialysate. Group 4 rats received AST-120, an oral adsorbent charcoal, mixed 5% by weight with standard rat chow and given ad libitum from 8 to 12 weeks after subtotal nephrectomy, while control Group 3 rats received only rat chow. Whole kidney GFR at 12 weeks was significantly higher in Group 2 PD versus Group 1 control (0.50 +/- 0.08 vs. 0.30 +/- 0.05 ml/min, P less than 0.05). There was no statistical difference for BUN and whole kidney creatinine or inulin clearance in Group 4 AST-120 treated versus Group 3 control rats. Light microscopic studies in autopsy specimens revealed that both PD and AST-120 attenuated progression of glomerular sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)