Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice

Abstract

. Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice. Am J Physiol Renal Physiol 290: F838 -F843, 2006. First published October 25, 2005 doi:10.1152/ajprenal.00374.2005.-NHERF-1 binds numerous renal protein targets, including the proximal tubule transporters Na ϩ /H ϩ exchanger 3 (NHE3) and Na ϩ -phosphate cotransporter 2a (Npt2a). Young NHERF-1 Ϫ/Ϫ male mice display defective targeting of Npt2a to apical membranes in the renal proximal tubule and manifest hypophosphatemia and increased urinary excretion of phosphate. The present studies describe the changes in the urinary excretion of phosphate, calcium, uric acid, and sodium in male and female wild-type and NHERF-1 null mice over a time period from 12 to 54 wk of age. Young male and female NHERF-1 Ϫ/Ϫ mice demonstrated increased urinary excretion of phosphate and urine phosphate/creatinine ratios. There was an age-related decline in the phosphate/ creatinine ratio in mutant mice such that there were no differences between wild-type and NHERF-1 Ϫ/Ϫ by 24 to 30 wk of age despite the continued presence of hypophosphatemia. Male and female NHERF-1 null mice also demonstrate increased urine calcium/creatinine and uric acid/creatinine ratios compared with wild-type controls. These studies indicate defects in the renal tubule transport of phosphate, calcium, and uric acid in NHERF-1 Ϫ/Ϫ male and female mice that could account for the increased deposition of calcium in the papilla of null mice. bone density and mineralization; hypophosphatemia; electrolyte excretion INACTIVATION OF THE GENE encoding the sodium-phosphate cotransporter 2a (Npt2a, NaPi IIa) results in increased urinary excretion of phosphate and calcium and a striking bone phenotype characterized by decreased bone density and mineralization (2). Interestingly, by mechanisms not well understood, the changes in bone resolve as the animals age. It has not been established, however, whether the changes in mineral excretion persist. Like the Npt2a null mouse, targeted gene deletion of the sodium-hydrogen exchanger regulator factor-1 (NHERF-1) results in animals with increased urinary excretion of phosphate and calcium (14). The present experiments were undertaken to determine whether there were age-related changes in the urinary excretion of phosphate, calcium, uric acid, and sodium in NHERF-1 Ϫ/Ϫ male and female animals. The results indicate that young male and female NHERF-1 null mice have increased urinary excretion of phosphate but that there is an age-related partial correction in the defect in phosphate transport. Both male and female NHERF-1 null mice also have increased urinary excretion of calcium and uric acid but, in contrast to the defect in phosphate excretion, the abnormalities persist throughout the period of observation up to 1 yr of age. The transient as well as the persistent changes in urinary mineral and electrolyte excretion in these mice predict urine prone to the formation of calcium and/or uric acid stones. Analysis of the mutant m...

Sodium-Hydrogen Exchanger Regulatory Factor-1 Interacts with Mouse Urate Transporter 1 to Regulate Renal Proximal Tubule Uric Acid Transport

“…Our previous studies indicated that NHERF-1 Ϫ/Ϫ mice have a significant increase in the urinary excretion of uric acid compared with wild-type control animals (6). To study the role of NHERF-1 on uric acid uptake in renal proximal tubule cells, we prepared primary cultures of proximal tubule cells using wildtype and NHERF-1 null mouse kidneys.…”

“…We recently reported that NHERF-1 Ϫ/Ϫ mice excrete increased amounts of uric acid compared with wild-type controls (6). These studies were initiated to define further the relation between this adaptor protein and uric acid excretion.…”

“…These adaptor proteins have multiple PSD-95/Dlg/ZO-1 (PDZ) protein interactive domains and, in the case of NHERF-1 and NHERF-2, a C-terminal domain that binds to ezrin, radixin, moesin, and merlin (1)(2)(3)(4). In mice, inactivation of the NHERF-1 gene, the founding member of this family, results in increased urinary excretion of phosphate as a result of decreased membrane abundance of the sodium-dependent phosphate co-transporter 2a (Npt2a), hypercalciuria as a result of the reciprocating changes in the plasma concentrations of 1,25 (OH) 2 vitamin D, and the interstitial deposition of calcium primarily in the papilla of the kidney (5,6). We also observed that both male and female NHERF-1 Ϫ/Ϫ mice have an increase in the urinary excretion of uric acid, the mechanism of which is unknown (6).…”

“…In mice, inactivation of the NHERF-1 gene, the founding member of this family, results in increased urinary excretion of phosphate as a result of decreased membrane abundance of the sodium-dependent phosphate co-transporter 2a (Npt2a), hypercalciuria as a result of the reciprocating changes in the plasma concentrations of 1,25 (OH) 2 vitamin D, and the interstitial deposition of calcium primarily in the papilla of the kidney (5,6). We also observed that both male and female NHERF-1 Ϫ/Ϫ mice have an increase in the urinary excretion of uric acid, the mechanism of which is unknown (6). Accordingly, these experiments were designed to study the relation between NHERF-1 and the renal transport of uric acid.…”

Animal models of urinary stone disease

“…NHERF-1 knockout mice have shown increased urinary calcium, phosphate, and uric acid excretion, resulting in tubulo-interstitial crystal deposits in the kidney [63]. Similar to NHEFR-1 mice, Npt2a knockout mice demonstrated hypercalciuria and renal crystal deposits in the kidney [54].…”