Few modulators have evolved that are dedicated to protecting against low phosphate conditions.1,2 The consequences of insufficient phosphate can be severe, and the lack of a system dedicated to maintaining an adequate phosphate level suggests it is a relatively rare occurrence. When non-mineralized phosphate does become low due to rapid bone mineralization, excess phosphatonin secretion, kidney disease, an insufficient diet, or poor absorption, a number of pathophysiological problems can occur. Chronic hypophosphatemia manifests as bone pain, muscle weakness, and failure to mineralize. Acute hypophosphatemia can develop during alkalosis, cytokine-induced hematopoiesis, or when intravenous administration of glucose is utilized as the sole source of energy. In all such cases, circulating phosphate enters cells to be consumed by cellular glycolysis. This results in limited oxidative phosphorylation and a deficit of 2,3 bisphosphoglycerate. The former dictates less ATP availability, which reduces overall metabolic activity. The latter disrupts the hemoglobin oxygen association/dissociation curve in erythrocytes. Thus, oxygen taken up in the lung is not efficiently released in the tissues, resulting in a generalized hypoxia.1 In light of these complications, it seems reasonable that some mechanism for phosphate “retention” must exist.
Circulating phosphate can be increased at the level of absorption. Vitamin D is believed to contribute to the appearance of phosphate transporters (NTP2b) on the luminal surface of intestinal epithelium.3,4 Alternatively, phosphate levels may be positively impacted by compounds at the level of renal reabsorption. Phosphate is considered freely filterable.5 Thus, renal regulation must be due to tubular absorption. Some factors that contribute to phosphate retention have been identified. They include the pleiotropic hormones IGF-I, growth hormone, thyroxine, and vitamin D.5 A fifth, and perhaps more kidney-specific hormone has recently been reported. Termed stanniocalcin-1 (STC-1), after its orthology to a fish hormone that shows anti-calcemic activity, it is a disulfide-linked homodimeric phosphoprotein.6,7 Much is unclear about this hormone. It is found in neurons, platelets/megakaryocytes, endothelial cells, and the nephron epithelium.8,9 It also has multiple targets including osteoblasts, neurons, and renal proximal tubule cells.8,10,11
|Figure 1. Elevated phosphate (Pi) stimulates the production of PTH that can bind to its receptor and initiate the internalization of phosphate transporters (NPT2a). PTH-induced elevations of extracellular Ca2+ may promote STC-1 production by renal collecting duct cells. In a paracrine fashion, it may then partially buffer the effects of PTH, potentially acting on proximal tubule cells and stimulating NPT2a transcription. This leads to phosphate uptake from glomerular filtrate.
What may be most compelling is the ability of STC-1 to (modestly) promote active phosphate uptake by renal proximal tubule cells.6,11,12 Given that it is apparently produced by the distal-epithelial components of the renal tubule, its actions could be paracrine in response to hypophosphatemia. However, this does not appear to be the case. Low levels of dietary phosphate actually decrease STC-1 mRNA, and circulating levels of phosphate measured during active renal STC-1-mediated phosphate resorption do not reach statistical significance. Thus, its physiological effects may be subtle at best. Intriguingly, its true activity may actually involve conditions of hyperphosphatemia (Figure 1). In this scenario, high phosphate levels promote the release of parathyroid hormone (PTH). PTH is known to induce the internalization of phosphate transporters (NPT2a), removing the vehicle for renal phosphate uptake. It is also able to increase calcium levels, an element that promotes STC-1 production. Once produced, STC-1 may begin to reverse (or modulate) the effects of PTH-induced NPT2a degradation. While its effect may be minor, it may buffer PTH-induced phosphate loss, and in a sense “promote resorption.” This potential relationship with PTH is not unlike the reciprocal relationship between insulin (glucose uptake) and glucagon (glucose release).12,13
- Bringhurst, F.R. & B.Z. Leder In Degroot (2006) L. J. & J.L. Jameson (eds): Endocrinology, 5th ed. Philadelphia, Elsevier, p. 1465.
- Prie, D. et al. (2005) Curr. Opin. Nephrol. Hypertens. 14:318.
- Goodman, W.G. (2005) Med. Clin. N. Am. 89:631.
- Berndt, T.J. et al. (2005) Am. J. Physiol. Renal Physiol. 289:F1170.
- Tenenhouse, H.S. (2005) Annu. Rev. Nutr. 25:197.
- Olsen, H.S. et al. (1996) Proc. Natl. Acad. Sci. USA 93:1792.
- Jellinek, D.A. et al. (2000) Biochem. J. 350:453.
- Serlachius, M. et al. (2004) Peptides 25:1657.
- Ishibashi, K. & M. Imai (2002) Am. J. Physiol. Renal Physiol. 282:F367.
- Yoshiko, Y. & J.E. Aubin (2004) Peptides 25:1663.
- Wagner, G.F. et al. (1997) J. Bone Miner. Res. 12:165.
- Yahata, K. et al. (2003) Biochem. Biophys. Res. Commun. 310:128.
- Deol, H. et al. (2001) Kidney Int. 60:2142.