SECONDARY HYPERPARATHYROIDISM AND VITAMIN-D-RECEPTOR BINDING TO VITAMIN-D RESPONSE ELEMENTS IN RATS WITH INCIPIENT RENAL-FAILURE

The pathogenesis of secondary hyperparathyroidism in early renal failu re is poorly understood. In the study presented here, parathyroid horm one and GFR in rats with mild renal failure of various durations are e valuated. Parathyroid hormone increased significantly 3 days after nep hrectomy and peaked at 2 wk, despite reduction in GFR of <50%. Parathy roid hormone remained elevated. but there was no difference in serum l evels of calcium, phosphorus, and calcitriol between the nephrectomize d and sham-operated rats. There were also no differences in both intes tinal and kidney vitamin D receptor concentrations between the two gro ups. Histomorphometric analysis of bone at 6 wk revealed significant i ncrease in osteoid thickness, osteoblast number, erosion surface with osteoclasts, and erosion depth. Employing electrophoretic mobility shi ft assay, we consistently observed a significant reduction in kidney c alcitriol-receptor complex binding to mouse osteopontin vitamin D resp onse element (-70.2 +/- 4.9%, P <0.001). Western blot analysis also re vealed a significant reduction in at least one retinoid X receptor iso form. In conclusion, biochemical and histological evidence of secondar y hyperparathyroidism develops in rats with mild renal failure, despit e normal calcium, phosphorus, calcitriol, and vitamin D receptor conce ntrations. These rats also have evidence of reduced renal vitamin D re ceptor binding to nuclear response elements. This finding, possibly an important early factor in the pathogenesis of secondary hyperparathyr oidism, could also play a role in the development of compensatory rena l growth of the remnant kidney.