| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
EDITORIAL FOCUS
Departments of 1Pediatrics, 3Physiology, and 2Nutritional Sciences, Steele Memorial Children's Research Center, College of Medicine, University of Arizona, Tucson, Arizona 85724
PHOSPHORUS (P) is a critical nutrient necessary for several key physiological processes in vertebrates, and P is also a structural component of several biological molecules. Thus an intimate knowledge of the regulation of body P homeostasis is important. Nutritional P deficiency occurs primarily in premature infants (7), and therefore, identifying genes involved in P homeostasis and understanding regulation of these genes by dietary P levels are of clinical relevance. In mammals, dietary P is absorbed predominantly by the type IIb sodium-phosphate (NaPi-IIb) cotransporter, which is expressed on the apical membrane of enterocytes in the small intestine (5). Similarly, renal P reabsorption is mediated by the type IIa sodium-phosphate (NaPi-IIa) cotransporter, which is expressed predominantly in the brush-border membranes of proximal tubular epithelial cells (8). Activity and expression of both of these transport proteins respond to dietary P deprivation by increasing activity to intake more P from dietary sources and to reabsorb more P from the renal filtrate (2, 6). Moreover, these cotransporters in mammals are positively regulated by 1,25-(OH)2-vitamin D3 (D3) (6, 13), and the vitamin D receptor (VDR) shows increased expression with low P intake (10). Furthermore, CYP27B1 [25-(OH) vitamin D-1
-hydroxylase] and CYP24 [25-(OH) vitamin D-24-hydroxylase], two enzymes involved in vitamin D3 metabolism, are also regulated by dietary P intake levels. During P deficiency, CYP27B1 is upregulated to produce the active vitamin D metabolite (1) and CYP24 is downregulated to prevent D3 catabolism (15). Two other genes that are responsive to P deprivation have recently been identified, Pi-uptake stimulator (PiUS) (9) and diphor-1 (4). However, the precise role of these proteins in P homeostasis is currently unknown.
Other than these known P-responsive genes described above, little is known about other genes that are regulated by dietary P levels and that may be involved in body P homeostasis. The paper by Sugiura and Ferraris (11) in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology specifically addresses this issue in the rainbow trout model. In addition to measuring the induction or repression of some known P-responsive genes in response to dietary P deprivation, these authors initiated extensive studies to identify novel P-responsive genes in the kidney, pyloric ceca (PC), and intestine of the rainbow trout. Being able to predict P deficiency in trout before the onset of phenotypical changes is important, as recent environmental mandates have required aquaculture facilities to reduce P levels in effluent water and thus P levels in fish diets are being reduced.
Although intestinal and renal morphology in the rainbow trout differ from that of mammals, there are some common characteristics. These commonalities include the physiological importance of intestinal Pi absorption, as rainbow trout do not absorb P from aqueous sources through the gills or skin because P is very low in freshwater (<0.1 mg/l). A type II NaPi cotransporter has been cloned from fish (14), and it is known to mediate P uptake in the intestine and kidney. Fish are thought to have only one type II NaPi cotransporter isoform that is expressed in both kidney and intestine and is likely a homolog of the NaPi-IIb gene in mammals (14). However, Sugiura and Ferraris (12) recently reported that there are two type II NaPi cotransporter isoforms in the rainbow trout. Furthermore, the NaPi-II cotransporter expressed in fish intestine and kidney is regulated by dietary P levels (3) and most likely by other hormones, in a similar fashion to regulation in mammalian species. In fish, it is currently unknown if D3 plays a role in regulating P uptake in intestine or reabsorption in kidney, but the Sugiura and Ferraris (11) study suggested that it may be important in renal P homeostasis. Few studies have investigated the regulation of P homeostasis in fish, so precise details have not been worked out as of yet. Overall, these facts suggest that the rainbow trout is a useful model to understand intestinal and renal mechanisms of P handling and that discoveries made in trout will likely also be relevant to mammalian systems.
Sugiura and Ferraris (11) first sought to determine the effect of P deprivation in trout on known P-responsive genes, including NaPi-II, PiUS, VDR, and CYP24 [25-(OH)vitamin D-24-hydroxylase]. Their results indicated that only intestinal NaPi-II showed marked responses to P deprivation up to 20 days, with the largest change noted in pyloric ceca. However, significant but smaller changes in mRNA expression were seen in the trout kidney, where NaPi-II, CYP24, and VDR were apparently coordinately regulated. These data suggested potential regulation of P reabsorption by D3 in the kidney. VDR expression did not change in the intestine with P deprivation, and PiUS mRNA expression slightly decreased in PC and kidney.
On the basis of the largely negative results of these studies, the authors then sought to identify novel genes regulated by dietary P, using a subtractive hybridization approach with intestinal, pyloric cecal, and renal cDNA libraries. Any genes identified might play novel roles in body P homeostasis and they could also serve as marker genes to predict pathological changes that precede clinical P deficiency. Analysis of over 1,200 subtracted cDNA clones and further downstream studies revealed 
30 P-responsive genes. Of these identified genes, many were only moderately regulated by dietary P (<2-fold); however, five genes showed more significant regulation. Interestingly, these five genes all showed increased expression (>2-fold), and the NaPi-II cotransporter, which increased almost 10-fold in PC, was one of these five genes. This finding suggested that these genes could play a direct role in P homeostasis, and because some of them showed significant increases after 2 or 5 days of P deprivation, it seems likely that they are involved in the initial response to low P diet rather than secondary to phenotypical changes associated with chronic P deprivation. The most strongly upregulated renal gene was one that had moderate homology to a family of S100 calcium-binding proteins. A potential role for this protein family in P homeostasis had not been previously described. Also in the kidney, a clone with significant homology to mitochondrial Pi carrier protein was induced threefold by low-P diet. As this protein transports Pi from the cellular cytosol to the mitochondrion for use in oxidative phosphorylation, this may be a vital compensatory response to P deprivation, which is known to decrease ATP production. In the intestine, a clone with 71% homology to rat meprin-1 was increased almost sixfold by low-P diet. Meprin is an apically expressed metalloendopeptidase, which also has not been previously associated with P homeostasis. Furthermore, in addition to upregulation of the NaPi-II cotransporter in the PC, a clone with low homology to salmon serum lectin was induced over sixfold by P deprivation. The exact identity of this gene and its potential role in P homeostasis is also currently unknown.
Overall, these novel studies by Sugiura and Ferraris identified potential candidate genes involved in intestinal and renal P homeostasis. As similar studies have not been performed to date in mammalian systems, the data presented in this paper have added significance. Although further studies to clearly identify and understand the function of these genes are necessary, it seems likely that some of these genes may be later shown to be of physiological significance in body P homeostasis. Additionally, investigation of how these genes may be involved in mammalian P (re)absorption is critical for a complete, detailed understanding of the biology of this critical molecule.
FOOTNOTES
Address for reprint requests and other correspondence: J. F. Collins, Depts. of Pediatrics and Nutritional Sciences, Steele Memorial Children's Research Center, College of Medicine, Univ. of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724 (E-mail: jcollins{at}peds.arizona.edu)
REFERENCES
-hydroxylase by phosphate depletion. J Biol Chem 251: 3158–3161, 1976.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
