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Time Course of Urinary Concentrating Defect in Vitamin D‐Induced Hypercalcemic Rats

We studied the onset of hypercalcemia‐induced nephrogenic diabetes insipidus and its relationship to aquaporin‐2 (AQP2) and bumetanide‐sensitive Na‐K‐2Cl cotransporter (NKCC2) expression. Rats were treated with or without food supplement of 1mg dihydrotachysterol (DHT)/kg BW/day for 1, 2, 7 days. After treatment for 1 day, serum calcium was significantly increased (control: 9.7±0.3 vs. DHT: 10.8±0.2 mg/dl). Urine volume was also significantly increased (0.27±0.18 vs. 0.83±0.14 ml/gram BW/day). Urine osmolality was decreased after 2 days of DHT ingestion (1.53±0.5 vs. 0.91±0.00 osmol/kgH2O, P < 0.05), suggesting DHT rats lose their ability to concentrate urine. Immunoblotting showed that NKCC2 abundance in kidney outer medulla of DHT‐treated rats was decreased by 59% after 1 day treatment and remained decreased until day 7. The AQP2 abundance in inner medulla was decreased by 44% after 2 days of DHT diet and remained decreased until day 7. In conclusion, the onset of polyuria and hypercalcemia were found to occur within 1 day after DHT treatment. The early development of polyuria in association with hypercalcemia was most likely due to a downregulation of NKCC2 in medullary thick ascending limb, whereas the urinary concentrating defect after 2 days DHT treatment involved downregulation of both NKCC2 and AQP2.