F1000Research 2017, 6(F1000 Faculty Rev):1797 Last updated: 17 JUL 2019 REVIEW Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule [version 1; peer review: 2 approved] Justin J. Lee1,2, Allein Plain1,2, Megan R. Beggs1,2, Henrik Dimke3, R. Todd Alexander 1,2,4 1Department of Physiology, University of Alberta, Edmonton, Canada 2The Women and Children’s Health Research Institute, Edmonton, Canada 3Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark 4Department of Pediatrics, Edmonton Clinic Health Academy, University of Alberta, Edmonton, Canada First published: 03 Oct 2017, 6(F1000 Faculty Rev):1797 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.12097.1) Latest published: 03 Oct 2017, 6(F1000 Faculty Rev):1797 ( https://doi.org/10.12688/f1000research.12097.1) Reviewer Status Abstract Invited Reviewers Calcium and phosphate are critical for a myriad of physiological and cellular 1 2 processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects version 1 of the phospho- and calciotropic hormones, parathyroid hormone (PTH), published active vitamin D3, and fibroblast growth factor 23 (FGF23). The organs 03 Oct 2017 central to this are the kidneys, intestine, and bone. In the kidney, the proximal tubule reabsorbs the majority of filtered calcium and phosphate, which amounts to more than 60% and 90%, respectively. The basic F1000 Faculty Reviews are written by members of molecular mechanisms responsible for phosphate reclamation are well the prestigious F1000 Faculty. They are described, and emerging work is delineating the molecular identity of the commissioned and are peer reviewed before paracellular shunt wherein calcium permeates the proximal tubular publication to ensure that the final, published version epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of is comprehensive and accessible. The reviewers who approved the final version are listed with their active vitamin D3 synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute names and affiliations. transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular 1 Orson Moe, University of Texas Southwestern mechanisms of calcium and phosphate reabsorption from the proximal Medical Center, Dallas, USA tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on University of Texas Southwestern Medical both renal calcium and phosphate handling as well as whole body mineral Center, Dallas, USA balance. 2 Olivier Bonny, Lausanne University Hospital, Keywords Lausanne, Switzerland Parathyroid hormone, fibroblast growth factor 23, phosphotropic University of Lausanne, Lausanne, Switzerland hormomes, calciotropic hormones Any comments on the article can be found at the end of the article. Page 1 of 14 F1000Research 2017, 6(F1000 Faculty Rev):1797 Last updated: 17 JUL 2019 Corresponding author: R. Todd Alexander ([email protected]) Author roles: Lee JJ: Conceptualization, Funding Acquisition, Writing – Review & Editing; Plain A: Conceptualization, Writing – Original Draft Preparation; Beggs MR: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Dimke H: Conceptualization, Writing – Review & Editing; Alexander RT: Conceptualization, Writing – Review & Editing Competing interests: The authors declare that they have no competing interests. Grant information: Work in the Alexander laboratory is funded by grants from the Women and Children’s Health Research Institute, which is supported by the Stollery Children’s Hospital Foundation, the Canadian Institutes of Health Research (MOP 136891), the National Sciences and Engineering Research Council, and the Kidney Foundation of Canada. HD is supported by Fabrikant Vilhelm Pedersen og Hustrus Mindelegat, the Novo Nordisk Foundation, the Carlsberg Foundation, the A.P. Møller Foundation, the Beckett Foundation, the Lundbeck Foundation, and the Danish Medical Research Council. MRB is supported by a Vanier Canada Graduate Scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2017 Lee JJ et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Lee JJ, Plain A, Beggs MR et al. Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule [version 1; peer review: 2 approved] F1000Research 2017, 6(F1000 Faculty Rev):1797 ( https://doi.org/10.12688/f1000research.12097.1) First published: 03 Oct 2017, 6(F1000 Faculty Rev):1797 (https://doi.org/10.12688/f1000research.12097.1) Page 2 of 14 F1000Research 2017, 6(F1000 Faculty Rev):1797 Last updated: 17 JUL 2019 Introduction About 65% of transepithelial sodium reabsorption in the nephron The kidneys play a critical role in maintaining electrolyte occurs in the PT, and two thirds of it occurs via the transcellular balance, including both calcium and phosphate. They accom- pathway in a process coupled to bicarbonate reclamation12,13. As plish this by adjusting the urinary excretion of these minerals, such, significant paracellular sodium reabsorption also takes place thereby amending the amount in blood. In particular, the proximal in this segment. Calcium reabsorption from the PT is primarily tubule (PT) reabsorbs approximately 70% of filtered calcium and mediated by the paracellular pathway, while phosphate reabsorp- 90% of filtered phosphate ions1. Failure to properly regulate PT tion occurs via the transcellular pathway14,15. Both calcium and reabsorption leads to abnormal calcium and phosphate homeos- phosphate reabsorption in the PT are dependent to some degree on tasis, which may manifest as neuromuscular, cardiovascular, or the transepithelial transport of sodium. gastrointestinal symptoms2. The molecular mechanisms mediating calcium and phosphate reabsorption in the PT, as well as the The proximal tubule, a target of calciophosphotropic endocrine regulation of these processes, have been extensively hormones studied. The endocrine factors involved in calcium and phos- Electrolyte transport in the PT is regulated by multiple factors, phate homeostasis are known as calciotropic and phosphotropic including the calciophosphotropic hormones PTH and FGF23. hormones, respectively. These hormones include parathyroid These hormones interdependently regulate one another through the hormone (PTH), 1,25-dihydroxyvitamin D (that is, active 3 PTH-active vitamin D–FGF23 axes (Figure 1)16. The regulatory vitamin D), and fibroblast growth factor 23 (FGF23). Previous mechanisms within these axes are complex and beyond the scope review articles have primarily focused on the individual effects of of this review. (The reader is referred to several recent reviews PTH, active vitamin D, and FGF23 on either calcium or phosphate covering this topic16–19.) Here, we focus on the effects of PTH, transport in the kidneys, and some have suggested an intercon- active vitamin D, and FGF23 on calcium and phosphate transport 1,3–6 nection between the two pathways . However, emerging work processes in the PT. demonstrates that PTH and FGF23 each have distinct effects on both phosphate and calcium homeostasis. They should thus be considered calciophosphotropic hormones, a term we will use PTH is produced in the parathyroid gland and released when for the remainder of this article. Here, we briefly review systemic calcium levels are reduced below the physiological set calcium and phosphate reabsorption and their dependence on point. PTH increases serum calcium levels by directly increas- sodium transport in the PT and then dissect the role of PTH and ing calcium resorption from bone and reabsorption from kidneys, FGF23 on these processes. while it indirectly stimulates intestinal absorption by increasing the synthesis of active vitamin D in the kidneys20–23. Concomi- Proximal tubule tantly, PTH inhibits phosphate reabsorption in the PT, thereby 24 The PT is the initial segment of the nephron wherein transport increasing phosphate excretion into urine . These actions on occurs. It is responsible for reabsorbing the majority of water the PT are mediated by its direct interaction with the G protein– and solutes that filter into this tubular segment from the glomer- coupled type 1 PTH receptors (PTHRs) expressed on both apical 25 ulus. Anatomically, the PT is located in the renal cortex and can and basolateral membranes . The major effects of PTH binding to be divided into (i) the proximal convoluted tubule (PCT) and (ii) the PTHR in the PT are mediated by protein kinase A (PKA) and the proximal straight tubule (PST). The PT can be further sub- protein kinase C (PKC). These protein kinases are stimulated by the G - and G -protein pathways, respectively26. It is noteworthy divided into segments S1, S2, and S3 on the basis of molecular s q/11 ultrastructure and expression profiles7–10. The PCT is comprised of that the apical PTHR preferentially signals