Electrolyte Blood Press.  2008 Dec;6(2):68-76. 10.5049/EBP.2008.6.2.68.

Kidney and Calcium Homeostasis

• Jeon US

• KMID: 2134808
• DOI: http://doi.org/10.5049/EBP.2008.6.2.68

Abstract

Plasma calcium concentration is maintained within a narrow range (8.5-10.5 mg/dL) by the coordinated action of parathyroid hormone (PTH), 1,25(OH)2D3, calcitonin, and ionized calcium (iCa2+) itself. The kidney plays a key role in this process by the fine regulation of calcium excretion. More than 95% of filtered calcium is reabsorbed along the renal tubules. In the proximal tubules, 60% of filtered calcium is reabsorbed by passive mechanisms. In the thick ascending limb, 15% of calcium is reabsorbed by paracellular diffusion through paracellin-1 (claudin-16). The calcium sensing receptor (CaSR) in the basolateral membrane of the thick ascending limb senses the change in iCa2+ and inhibits calcium reabsorption independent to PTH and 1,25(OH)2D3. The fine regulation of calcium excretion occurs in the distal convoluted tubules and connecting tubules despite the fact that only 10-15% of filtered calcium is reabsorbed there. Transient receptor potential vanilloid 5 (TRPV5) and 6 (TRPV6) in the apical membrane act as the main portal of entry, calbindin-D28K delivers Ca2+ in the cytoplasm, and then Na2+/Ca2+ exchanger (NCX1) and plasma membrane Ca2+-ATPase in the basolateral membrane serve as an exit. In the cortical collecting duct, TRPV6 is expressed, but the role might be negligible. In addition to PTH and 1,25(OH)2D3, acid-base disturbance, diuretics, and estrogen affect on these calcium channels. Recently, klotho and fibroblast growth factor 23 (FGF23) are suggested as new players in the calcium metabolism. Klotho is exclusively expressed in the kidney and co-localized with TRPV5, NCX1, and calbindin-D28K. Klotho increases calcium reabsorption through trafficking of TRPV5 to the plasma membrane, and also converts FGF receptor to the specific FGF23 receptor. FGF23:klotho complex bound to FGF receptor inhibits 1alpha- hydroxylase of vitamin D, and contributes to calcium reabsorption and phosphate excretion in the kidney.

MeSH Terms

Calcitonin
Calcium
Calcium Channels
Calcium-Binding Protein, Vitamin D-Dependent
Cell Membrane
Cytoplasm
Diffusion
Diuretics
Estrogens
Extremities
Fibroblast Growth Factors
Homeostasis
Kidney
Membranes
Parathyroid Hormone
Plasma
Receptors, Calcium-Sensing
Receptors, Fibroblast Growth Factor
TRPV Cation Channels
Vitamin D
Calcitonin
Calcium
Calcium Channels
Calcium-Binding Protein, Vitamin D-Dependent
Diuretics
Estrogens
Fibroblast Growth Factors
Parathyroid Hormone
Receptors, Calcium-Sensing
Receptors, Fibroblast Growth Factor
TRPV Cation Channels
Vitamin D

Figure

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  Fig. 1 Ca2+ absorption in the thick ascending limb of Henle (TAL). (a) The schematic view of Ca2+ reabsorption in the TAL. Paracellin-1 (claudin-16) is located in the tight junction of TAL and serves as the paracellular route for divalent cations. (b) Immunofluorescence image for paracellin-1 (claudin-16) in the mouse TAL cells. Paracellin-1 is co-localized with THP (the marker of TAL) and highly expressed in the tight junction1). BSC1, bumetanide sensitive channel; ROMK, renal outer medullary potassium channel; ClCNKB, chloride channel Kb.

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  Fig. 2 The mechanism of Ca2+ absorption in the renal epithelium. Transcellular Ca2+ reabsorption in the distal convoluted tubule (DCT) and connecting tubule (CNT) occurs by three steps; (i) entry of Ca2+ through the calcium channels [transient receptor potential vanilloid (TRPV) 5, TRPV6] in the apical membrane, (ii) binding of Ca2+ with calcium-binding protein (calbindin) and diffusion in the cytoplasm (without significant change in the intracellular i[Ca2+]), and (iii) Ca2+ extrusion via an ATP-dependent Ca2+-ATPase (PMCA1b) or an Na2+/Ca2+ exchanger (NCX1) in the basolateral membrane.

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  Fig. 3 Ca2+ transport proteins in the distal convoluted tubule (DCT) and connecting tubule (CNT). (a) The molecular structure of transient receptor potential vanilloid (TRPV) 5 and TRPV6. TRPV 5/6 consists of six transmembrane domains and ankyrin repeat at the N-terminal. The functional pore is composed with TM5 and TM6 of the tetramer2). (b) TRPV5 is exclusively expressed in the apical membrane of the DCT and CNT cells (especially DCT-2). TRPV6 is co-localized with TRPV5, but also observed in the collecting duct (the lower panel). Na+/Cl- cotransporter (NCC) is the DCT and CNT marker10, 11). ECaC, epithelial calcilulm channel 1 (TRPV5); NCX, Na2+/Ca2+ exchanger; CaBP28K, calbindin-D28K; AQP2, aquaporin 2.

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  Fig. 4 The summary of the distribution of major renal calcium transport proteins. G, glomerulus; PCT, proximal convoluted tubule; PST, proximal straight tubule; S1, segment 1; S2, segment 2; S3, segment 3; DTL, descending thin limb; ATL, ascending thin limb; mTAL, medullary thick ascending limb; cTAL, cortical thick ascending limb; MD, macula densa; DCT, distal convoluted tubule; CNT, connecting tubule; ICD, initial collecting duct; CCD cortical collecting duct; OMCD, outer medullary collecting duct; IMCD, inner medullary collecting duct; TRPV, transient receptor potential vallinoid; PMCA1b, plasma membrane Ca2+-ATPase; NCX1, Na2+/Ca2+ exchanger; NCC, Na+/Cl- cotransporter; AQP2, aquaporin 2.

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  Fig. 5 Klotho in the kidney. (a) The renal distribution of klotho proteins. Klotho is co-expressed with transient receptor potential vallinoid 5 (TRPV5), Na2+/Ca2+ exchanger (NCX1) and calbindin-D28K in the distal convoluted tubule (DCT) and connecting tubule (CNT) 20). (b) The suggested mechanism of the regulation of calcium homeostasis by klotho. PTH, parathyroid hormone; FGF23, fibroblast growth factor 23.

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  Fig. 6 Fibroblast growth factor 23 (FGF23) in the kidney. (a) The structure of FGF23 proteins. The full length of FGF23 is about 30 kDa, and then inactivated by cleavage to 18 kDa N-terminal fragment and 12 kDa C-terminal fragment24). (b) Suggested mechanism of the FGF23:klotho complex action; Klotho binds to FGF receptor (FGFR) and converts it to a specific receptor for FGF23. Extracellular signalregulated kinase (ERK) 1/2 signaling pathway is activated by binding of the FGF23:klotho complex to FGFR. The FGF23:klotho complex reduces phosphate reabsorption in the proximal tubules via the inhibition of 1α-hydrxylase and NaPi-2a. It might also stimulate parathyroid hormone (PTH) secretion in parathyroid glands. NaPi-2a/c, Type IIa/IIc Na+/Pi contransporter.

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