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The effect of phosphorylated phloretins on Na(+)-dependent phosphate uptake into rabbit renal brush-border membrane vesicles (BBMV) was examined. Na(+)-dependent phosphate uptake into isolated rabbit cortex BBMV was sensitive to 2'-phosphophloretin (2'-PP) and 2'-phospho-4',4,6'-trimethoxy phloretin (PTMP) in a dose-dependent and pH-dependent manner. PTMP inhibition of Na(+)-dependent phosphate uptake was maximum at alkali pH, and 2'-PP inhibition of Na(+)-dependent phosphate uptake was maximum at acidic pH. Increasing Na(+) concentrations did not increase PTMP inhibition of renal cortex BBMV Na(+)-dependent phosphate uptake at pH 6. The effect of phosphophloretins on Na(+)-dependent phosphate uptake was examined in BBMV isolated from purified proximal tubules and distal tubules. 2'-PP and PTMP inhibition of Na(+)-dependent phosphate uptake into BBMV isolated from purified proximal tubules was similar to the inhibition seen with BBMV from renal cortex. 2'-PP, but not PTMP, inhibited Na(+)-dependent phosphate uptake into BBMV isolated from purified distal tubules. The pH dependence of inhibition, the absence of PTMP inhibition of Na(+)-dependent phosphate uptake into distal tubule BBMV, and the inhibition of Na(+)-dependent phosphate uptake into distal tubule BBMV suggest that NaPi-Ia is 2'-PP sensitive and NaPi-IIa is PTMP sensitive.

Hyperhosphatemia and secondary hyperparathyroidism are common and severe complications of chronic renal failure. Therapies to reduce serum phosphate have been shown to reduce serum parathyroid hormone (PTH) and slow the progression of renal failure. The effect of the inhibitor of intestinal phosphate absorption, 2'-phosphophloretin (2'-PP), on serum and urine chemistry, renal histology, and cardiac structure in the uremic rat model of renal failure, 5/6 nephrectomy (5/6 NX), was examined. The effect of 2'-PP on serum phosphate, serum PTH, serum total Ca(2+), and ionized Ca(2+), Ca(2+) x P(i) product, urine protein, urine osmolality, and creatinine clearance in 5/6 NX rats was examined. Uremic rats in chronic renal failure were gavaged daily with 25 microM 2'-PP. Over the course of a 5-wk experiment, serum chemistry in untreated uremic rats, 2'-PP-treated uremic rats, and age-matched control rats with normal renal function was determined twice a week. Urine creatinine, urine osmolality, urine phosphate, and urine protein were determined once a week from 24-h collections. 2'-PP reduced serum phosphate 40 +/- 3% compared with a 17% increase in untreated uremic control rats. 2'-PP did not alter total serum Ca(2+). During 5-wk experiments, serum PTH increased 65 +/- 25% in untreated uremic rats and decreased 70 +/- 7% in uremic rats treated with 25 microM 2'-PP. Creatinine clearance decreased 20% in untreated uremic rats compared with a 100% increase in 2'-PP-treated uremic rats. Urine protein decreased and urine osmolality increased in uremic rats treated with 2'-PP. The mechanism of the effect of 2'-PP on serum phosphate was inhibition of intestinal phosphate absorption. 2-PP inhibited intestinal phosphate absorption 50% without altering dietary protein absorption or intestinal Ca(2+) absorption. Over the course of the 5-wk treatment with 2'-PP, uremic animals treated with 2'-PP had a 2-4% weight gain/wk, similar to the weight gain seen in age-matched control rats with normal renal function.