Coordinated control of renal Ca2+ transport proteins by parathyroid hormone

被引:134
作者
van Abel, M
Hoenderop, JGJ
van der Kemp, AWCM
Friedlaender, MM
van Leeuwen, JPTM
Bindels, RJM
机构
[1] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Dept Physiol, NL-6500 HB Nijmegen, Netherlands
[2] Hadassah Univ Hosp, Nephrol & Hypertens Serv, IL-91120 Jerusalem, Israel
[3] Erasmus Sch Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands
关键词
ECaC; TRPV5; TRPV6; PTH; Ca2+-sensing receptor; calcimimetic; NPS R-467; ruthenium red;
D O I
10.1111/j.1523-1755.2005.00587.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background. The kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca2+ handling in these disorders is poorly understood. Methods. Parathyroidectomized and PTH-supplemented rats and mice infused with the calcimimetic compound NPS R-467 were used to study the in vivo effect of PTH on the expression of renal transcellular Ca2+ transport proteins, including the epithelial Ca2+ channel transient receptor potential, vanilloid, member 5 (TRPV5), calbindins, and the Na+/Ca2+-exchanger (NCX1). In addition, the effect of PTH on transepithelial Ca2+ transport in rabbit connecting tubule/cortical collecting duct (CNT/CCD) primary cultures was determined. Results. Decreased PTH levels in parathyroidectomized rats or NPS R-467-infused mice, resulted in reduced expression of these proteins, which is consistent with diminished Ca2+ reabsorption, causing the development of the observed hypocalcemia. PTH supplementation of parathyroidectomized rats restored the expression of the renal Ca2+ transport machinery and serum Ca2+ levels, independent of serum 1,25-dihydroxyvitamin D-3 levels and renal vitamin D or Ca2+-sensing receptor mRNA abundance. Inhibition of the PTH-stimulated transepithelial Ca2+ transport by the TRPV5-specific inhibitor ruthenium red reduced the PTH-stimulated expression of calbindin-D-28K and NCX1 in rabbit CNT/CCD primary cultures. Conclusion. PTH stimulates renal Ca2+ reabsorption through the coordinated expression of renal transcellular Ca2+ transport proteins. Moreover, the PTH-induced stimulation is enhanced by the magnitude of the Ca2+ influx through the gatekeeper TRPV5, which in turn facilitates the expression of the downstream Ca2+ transport proteins. Therefore, the renal transcellular Ca2+ transport proteins, including TRPV5, could contribute to the pathogenesis of PTH-related disorders.
引用
收藏
页码:1708 / 1721
页数:14
相关论文
共 41 条
[1]   Calcium-sensing receptor regulation of renal mineral ion transport [J].
Ba, JM ;
Friedman, PA .
CELL CALCIUM, 2004, 35 (03) :229-237
[2]   ACTIVE CA-2+ TRANSPORT IN PRIMARY CULTURES OF RABBIT KIDNEY CCD - STIMULATION BY 1,25-DIHYDROXYVITAMIN-D3 AND PTH [J].
BINDELS, RJM ;
HARTOG, A ;
TIMMERMANS, J ;
VANOS, CH .
AMERICAN JOURNAL OF PHYSIOLOGY, 1991, 261 (05) :F799-F807
[3]  
BINDELS RJM, 1993, J EXP BIOL, V184, P89
[4]   EFFECT OF PROTEIN-KINASE-C ACTIVATION AND DOWN-REGULATION ON ACTIVE CALCIUM-TRANSPORT [J].
BINDELS, RJM ;
DEMPSTER, JA ;
RAMAKERS, PLM ;
WILLEMS, PHGM ;
VANOS, CH .
KIDNEY INTERNATIONAL, 1993, 43 (02) :295-300
[5]   EFFECTS OF PH ON APICAL CALCIUM-ENTRY AND ACTIVE CALCIUM-TRANSPORT IN RABBIT CORTICAL COLLECTING SYSTEM [J].
BINDELS, RJM ;
HARTOG, A ;
ABRAHAMSE, SL ;
VANOS, CH .
AMERICAN JOURNAL OF PHYSIOLOGY, 1994, 266 (04) :F620-F627
[6]   Vitamin D [J].
Brown, AJ ;
Dusso, A ;
Slatopolsky, E .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1999, 277 (02) :F157-F175
[7]   CLONING AND CHARACTERIZATION OF AN EXTRACELLULAR CA2+-SENSING RECEPTOR FROM BOVINE PARATHYROID [J].
BROWN, EM ;
GAMBA, G ;
RICCARDI, D ;
LOMBARDI, M ;
BUTTERS, R ;
KIFOR, O ;
SUN, A ;
HEDIGER, MA ;
LYTTON, J ;
HEBERT, SC .
NATURE, 1993, 366 (6455) :575-580
[8]   Extracellular calcium sensing and extracellular calcium signaling [J].
Brown, EM ;
MacLeod, RJ .
PHYSIOLOGICAL REVIEWS, 2001, 81 (01) :239-297
[9]   Evidence for involvement of 17β-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the rat [J].
Colin, EM ;
Van den Bemd, GJCM ;
Van Aken, M ;
Christakos, S ;
De Jonge, HR ;
DeLuca, HF ;
Prahl, JM ;
Birkenhäger, JC ;
Buurman, CJ ;
Pols, HAP ;
van Leeuwen, JPTM .
JOURNAL OF BONE AND MINERAL RESEARCH, 1999, 14 (01) :57-64
[10]   RESPONSE OF PHOSPHATE TRANSPORT TO PARATHYROID-HORMONE IN SEGMENTS OF RABBIT NEPHRON [J].
DENNIS, VW ;
BELLOREUSS, E ;
ROBINSON, RR .
AMERICAN JOURNAL OF PHYSIOLOGY, 1977, 233 (01) :F29-F38