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      Regulation of the Renal Sodium-Dependent Phosphate Cotransporter NaPi 2 (Npt2) in Acute Renal Failure due to Ischemia and Reperfusion

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          Background: Acute renal failure (ARF) is associated with hyperphosphatemia and decreased urinary phosphate excretion. The present study was undertaken to characterize the effects of ARF due to ischemia and reperfusion on renal phosphate transport and on gene and pro- tein expression of type IIa NaPi cotransporter (Npt2) the physiologically most relevant renal sodium-dependent phosphate cotransporter. Methods: The following groups of rats with intact parathyroid glands were studied: (1) sham operated (sham); (2) after 1 h ischemia by bilateral renal artery clamping (I), and after 1 h ischemia and reperfusion of 1 h (I + R 1 h); (3) 24 h (I + R 24 h); (4) 48 h (I + R 48 h), and (5) 72 h (I + R 72 h) duration. The effect of ARF on Npt2 mRNA and protein expression was also examined after parathyroidectomy (PTX) of 2 and 4 days’ duration. Results: Ischemia and reperfusion were associated with increases in plasma creatinine, hyperphosphatemia, and with decreased tubular phosphate reabsorption. Npt2 mRNA was significantly downregulated in the cortex, maximal at 24 and 48 h of reperfusion. The degree of Npt2 mRNA downregulation was not affected by PTX of 2–4 days’ duration. The abundance of Npt2 protein in proximal tubular apical brush border membrane was markedly decreased after reperfusion. Npt2 protein, however, was more abundant in PTX animals than in those with intact parathyroids and a similar degree of renal insufficiency. The immunohistochemical analysis of proximal tubular apical brush border membrane showed a progressive decrease of Npt2 protein labeling after ischemia and reperfusion, with progressive regeneration after 72 h. Conclusion: These results suggest that downregulation of Npt2 protein may contribute to the decreased tubular reabsorption of phosphate in acute ischemic renal failure and hyperphosphatemia.

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          Most cited references 25

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          Recent advances in the pathophysiology of ischemic acute renal failure.

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            Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities.

            Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (Pi) cotransporter that is expressed in the proximal tubule where the bulk of filtered Pi is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of Pi homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal Pi reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhibit increased urinary Pi excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal Pi reabsorption. However, unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia. At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype. Our findings demonstrate that Npt2 is a major regulator of Pi homeostasis and necessary for normal skeletal development.
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              Growth-related renal type II Na/Pi cotransporter.

              Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na(+)-dependent inorganic phosphate (P(i)) cotransporter (type IIc). Microinjection of type IIc cRNA into Xenopus oocytes demonstrated sodium-dependent P(i) cotransport activity. Affinity for P(i) was 0.07 mm in 100 mm Na(+). The transport activity was dependent on extracellular pH. In electrophysiological studies, type IIc Na/P(i) cotransport was electroneutral, whereas type IIa was highly electrogenic. In Northern blotting analysis, the type IIc transcript was only expressed in the kidney and highly in weaning animals. In immunohistochemical analysis, the type IIc protein was shown to be localized at the apical membrane of the proximal tubular cells in superficial and midcortical nephrons of weaning rat kidney. Hybrid depletion experiments suggested that type IIc could function as a Na/P(i) cotransporter in weaning animals, but its role is reduced in adults. The finding of the present study suggest that the type IIc is a growth-related renal Na/P(i) cotransporter, which has a high affinity for P(i) and is electroneutral.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                May 2005
                21 April 2005
                : 100
                : 1
                : p1-p12
                aHadassah University Hospital, Jerusalem, Israel; bUniversity of Texas Southwestern Medical Center at Dallas and VAMC, Dallas, Tex., and cUniversity of Colorado Health Sciences Center and VAMC, Denver, Colo., USA
                84463 Nephron Physiol 2005;100:p1–p12
                © 2005 S. Karger AG, Basel

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                Figures: 11, Tables: 1, References: 47, Pages: 1
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