Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Abstract

Abstract. The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A␤ gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1␣-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.Phosphate (Pi) homeostasis is essential to life and is dependent on active renal reabsorption. In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2). The kidney has an intrinsic P sensing system that regulates the activity of apical brush border membrane type II Na/Pi co-transporters (3). However, it is still not known how the organism senses changes in serum P.There are three mammalian Na/Pi co-transporter families: types I through III. Type II Na/Pi activity is responsible for Ͼ80% of renal P reabsorption and contains three isoforms-IIa through c-of which IIa is the major factor in renal P reabsorption and regulation in adult mice (4). Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11). In the rat, a cis acting element in the type II Na/Pi co-transporter (Na/Pi-2) mRNA at the junction of the coding region and the 3'-untranslated region (UTR) interacts with trans acting renal cytosolic proteins and determines Na/Pi-2 mRNA stability in response to dietary P restriction (12). An additional level of regulation of Na/Pi-2 is its translational control by a low-P diet (10).The renal type II Na/Pi co-transporte...

Recovery of Hyperphosphatoninism and Renal Phosphorus Wasting One Year after Successful Renal Transplantation

“…This observation questions the thesis that calcineurin inhibitor therapy contributes substan- tially to renal phosphorus wasting in the first year after transplantation, as advanced by others (30,31). Our data also suggest that the role of renal phosphorus wasting in the pathogenesis of posttransplant bone mineral density losses declines with time after transplantation.…”

Increased Parathyroid Hormone Gene Expression in Secondary Hyperparathyroidism of Experimental Uremia Is Reversed by Calcimimetics

“…Moreover, calcineurin A␤ knockout mice had higher basal levels of PTH mRNA, suggesting that calcineurin A␤ is essential to PTH gene expression (14). It is interesting that calcineurin A␤ also determined the response of the renal Na/Pi type II co-transporter to changes in serum phosphate (21), suggesting an important role for Ca 2ϩ calmodulin activation of calcineurin in the signal transduction after changes in serum Ca 2ϩ and phosphate.…”

Functional characterization of the Aspergillus fumigatus PHO80 homologue

“…Here, we have observed an interaction between DphoB PHO80 mutant, cyclosporin A-sensitivity and calcium-tolerance. The influence of calcineurin on phosphate transport has already been observed in the renal type II Na/P i co-transporter (Moz et al, 2004). Mice with genetic deletion of the calcineurin A b gene had a marked decrease in type II Na/P i mRNA levels and remarkably did not show the expected increase in type II Na/P i mRNA levels after the challenge of a low-P i diet.…”