Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule

Abstract

Calcium and phosphate are critical for a myriad of physiological and cellular processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects of the phospho- and calciotropic hormones, parathyroid hormone (PTH), active vitamin D ₃, and fibroblast growth factor 23 (FGF23). The organs 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 molecular mechanisms responsible for phosphate reclamation are well described, and emerging work is delineating the molecular identity of the paracellular shunt wherein calcium permeates the proximal tubular epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of active vitamin D ₃ synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular mechanisms of calcium and phosphate reabsorption from the proximal tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on both renal calcium and phosphate handling as well as whole body mineral balance.

Keywords: Parathyroid hormone; calciotropic hormones; fibroblast growth factor 23; phosphotropic hormomes.

Figure 1.. Regulation of calcium and phosphate by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D ₃ (active vitamin D), and fibroblast growth factor 23 (FGF23).

( A) Low plasma calcium stimulates release of PTH from the parathyroid glands. PTH stimulates resorption of bone, releasing calcium and phosphate into the plasma. In the kidney, PTH increases urinary calcium reabsorption and phosphate excretion. ( B) PTH-dependent active calcium reabsorption takes place in the distal nephron but, in the proximal tubule (PT), stimulates 1α-hydroxylase to convert 25-hydroxyvitamin D ₃ into active vitamin D and reduces the reabsorption of sodium, calcium, and phosphate. Active vitamin D increases calcium absorption from the small intestine and stimulates FGF23 secretion from bone. ( C) FGF23 acts as a negative feedback modulator of activated vitamin D activation and increases distal nephron calcium reabsorption while decreasing phosphate reabsorption from PT.

Figure 2.. Proximal tubule (PT) calcium (Ca ²⁺) reabsorption.

( A) Calcium reabsorption from the PT occurs primarily by a paracellular route, likely mediated by claudin-2 (CLDN2). This is dependent on transcellular sodium reabsorption, driven by the sodium proton exchanger (NHE3) and sodium potassium ATPases. The reabsorption of sodium generates an osmotic gradient for water reabsorption, which in turn drags other solutes (including calcium) in a process known as solvent drag (top junction). In the late PT, the calcium concentration gradient favours reabsorption (from apical to basolateral) as the majority of sodium and water reabsorption occurs in the early PT (bottom junction). The transcellular calcium reabsorption pathway, present in late PT, is illustrated as a dashed line. ( B) Parathyroid hormone (PTH) in the PT decreases calcium reabsorption by attenuating its driving force. PTH in both the tubular fluid and the blood binds its receptor (PTHR), which is expressed on both apical and basolateral membranes. This activates the downstream messengers protein kinase A (PKA) and protein kinase C (PKC). Note that apical PTHR preferentially activates PKC. Both pathways inhibit NHE3 activity and reduce abundance, but only PKC inhibits Na ⁺/K ⁺ ATPase activity. PTH also reduces tight-junction permeability in the PT and enhances active vitamin D ₃ synthesis. In contrast, fibroblast growth factor 23 (FGF23) reduces active vitamin D ₃ levels.

Figure 3.. Proximal tubule (PT) phosphate reabsorption.

( A) Phosphate reabsorption in the PT is mediated by the transcellular pathway. Apical entry occurs through the sodium-phosphate exchanger family (NaPi) subtypes IIa and IIc and sodium-dependent phosphate transporter 2 (PiT-2). The stoichiometric ratio and preference of phosphate species are depicted. The basolateral extrusion of phosphate may occur through the xenotropic and polytropic retroviral receptor (XPR1). ( B) Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both attenuate phosphate reabsorption in the PT by inhibiting NaPi-II cotransporters. PTH in the tubular fluid and blood activates protein kinase A and C (PKA and PKC). These kinases phosphorylate the PDZ domain–containing scaffold protein sodium hydrogen exchanger regulatory factor 1 (NHERF1), leading to internalization and degradation of NaPi-IIa. FGF23 in the blood binds to its receptor complex (which includes the cofactor, klotho). This leads to the activation of the mitogen-activated protein kinase (MAPK) pathway, resulting in phosphorylation of NHERF1. This signal cascade also decreases NaPi-IIa abundance. How PTH and FGF affect NaPi-IIc is currently unknown.