甲状旁腺激素1型受体在肾脏疾病中的研究进展

doi:10.12114/j.issn.1007-9572.2022.0523

摘要/Abstract

摘要： 甲状旁腺激素1型受体（PTH1R）是G蛋白偶联受体家族成员之一，在体内广泛表达，参与体内胚胎发育、钙磷稳态、机体代谢、肿瘤发生等多种过程。PTH1R在肾脏中高度表达，PTH1R的活化可涉及多种复杂机制，参与肾脏疾病的发生、发展，与多种肾脏疾病如糖尿病肾病、肾小球肾炎、急性肾损伤、慢性肾脏病等关系密切。本文就PTH1R功能及其在肾脏疾病中发挥的作用和机制进行综述，深入探讨PTH1R与肾脏疾病的关系和相关机制，以期为肾脏疾病的诊断和治疗提供新思路。

关键词: 肾疾病, 受体，甲状旁腺激素，1型, 甲状旁腺激素相关蛋白质, 甲状旁腺激素, 糖尿病肾病, 肾小球肾炎, 慢性肾脏病, 急性肾损伤, 综述

Abstract:

Parathyroid hormone type 1 receptor (PTH1R), a member of the G-protein-coupled receptor family, is extensively expressed in the human body and is involved in various processes such as embryonic development, calcium and phosphorus homeostasis, body metabolism and tumorigenesis. PTH1R is highly expressed in the kidney, and its activation is involved in the development and progression of renal diseases though multiple mechanisms and complicated pathways, and is closely associated with a variety of renal diseases such as diabetic nephropathy, glomerulonephritis, acute kidney injury, and chronic kidney disease. This article reviews recent studies about the function of PTH1R, and its role and mechanism of action in renal diseases, and provides an in-depth discussion on the relationship and related mechanisms between PTH1R and kidney diseases, offering new ideas for the diagnosis and treatment of kidney diseases.

Key words: Kidney diseases, Receptor, parathyroid hormone, type 1, Parathyroid hormone-related protein, Parathyroid hormone, Diabetic nephropathies, Glomerulonephritis, Chronic kidney disease, Acute kidney injury, Review

鄢鹏,宋健玲,房向东. 甲状旁腺激素1型受体在肾脏疾病中的研究进展[J]. 中国全科医学, 2023, 26(11): 1398-1403. DOI: 10.12114/j.issn.1007-9572.2022.0523.
YAN Peng,SONG Jianling,FANG Xiangdong. Recent Developments in Parathyroid Hormone Type 1 Receptor and Kidney Disease[J]. Chinese General Practice, 2023, 26(11): 1398-1403. DOI: 10.12114/j.issn.1007-9572.2022.0523.

参考文献 51

[1]	PINHEIRO P L, CARDOSO J C, POWER D M，et al. Functional characterization and evolution of PTH/PTHrP receptors：insights from the chicken[J]. BMC Evol Biol，2012，12:110. DOI：10.1186/1471-2148-12-110.
[2]	CLEMENS T L, CORMIER S, EICHINGER A，et al. Parathyroid hormone-related protein and its receptors：nuclear functions and roles in the renal and cardiovascular systems，the placental trophoblasts and the pancreatic islets[J]. Br J Pharmacol，2001，134(6):1113-1136. DOI：10.1038/sj.bjp.0704378.
[3]	BURTIS W J, WU T, BUNCH C，et al. Identification of a novel 17，000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy[J]. J Biol Chem，1987，262(15):7151-7156.
[4]	MCCAULEY L K, MARTIN T J. Twenty-five years of PTHrP progress：from cancer hormone to multifunctional cytokine[J]. J Bone Miner Res，2012，27(6):1231-1239. DOI：10.1002/jbmr.1617.
[5]	PIOSZAK A A, PARKER N R, GARDELLA T J，et al. Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides[J]. J Biol Chem，2009，284(41):28382-28391. DOI：10.1074/jbc.M109.022905.
[6]	CHELOHA R W, GELLMAN S H, VILARDAGA J P，et al. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects[J]. Nat Rev Endocrinol，2015，11(12):712-724. DOI：10.1038/nrendo.2015.139.
[7]	PAL K, MELCHER K, XU H E. Structure and mechanism for recognition of peptide hormones by Class B G-protein-coupled receptors[J]. Acta Pharmacol Sin，2012，33(3):300-311. DOI：10.1038/aps.2011.170.
[8]	CASTRO M, NIKOLAEV V O, PALM D，et al. Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism[J]. Proc Natl Acad Sci USA，2005，102(44):16084-16089. DOI：10.1073/pnas.0503942102.
[9]	ZINDEL D, ENGEL S, BOTTRILL A R，et al. Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling[J]. Biochem J，2016，473(22):4173-4192. DOI：10.1042/BCJ20160740.
[10]	MAHON M J, DONOWITZ M, YUN C C，et al. Na（+）/H（+）exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling[J]. Nature，2002，417(6891):858-861. DOI：10.1038/nature00816.
[11]	SINGH A T K, GILCHRIST A, VOYNO-YASENETSKAYA T，et al. G alpha12/G alpha13 subunits of heterotrimeric G proteins mediate parathyroid hormone activation of phospholipase D in UMR-106 osteoblastic cells[J]. Endocrinology，2005，146(5):2171-2175. DOI：10.1210/en.2004-1283.
[12]	GESTY-PALMER D, CHEN M Y, REITER E，et al. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation[J]. J Biol Chem，2006，281(16):10856-10864. DOI：10.1074/jbc.M513380200.
[13]	SYME C A, FRIEDMAN P A, BISELLO A. Parathyroid hormone receptor trafficking contributes to the activation of extracellular signal-regulated kinases but is not required for regulation of cAMP signaling[J]. J Biol Chem，2005，280(12):11281-11288. DOI：10.1074/jbc.M413393200.
[14]	LYU P, LI B, LI P R，et al. Parathyroid hormone 1 receptor signaling in dental mesenchymal stem cells：basic and clinical implications[J]. Front Cell Dev Biol，2021，9:654715. DOI：10.3389/fcell.2021.654715.
[15]	IZQUIERDO-LAHUERTA A. The parathyroid hormone-related protein/parathyroid hormone 1 receptor axis in adipose tissue[J]. Biomolecules，2021，11(11):1570. DOI：10.3390/biom11111570.
[16]	PILZ P, MEYER-MARCOTTY P, EIGENTHALER M，et al. Differential diagnosis of primary failure of eruption（PFE）with and without evidence of pathogenic mutations in the PTHR1 gene[J]. J Orofac Orthop，2014，75(3):226-239. DOI：10.1007/s00056-014-0215-y.
[17]	FU X K, ZHOU B, YAN Q N，et al. Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice[J]. Signal Transduct Target Ther，2020，5(1):297. DOI：10.1038/s41392-020-00328-y.
[18]	ORTEGA A, PÉREZ DE PRADA M T, MATEOS-CÁCERES P J，et al. Effect of parathyroid-hormone-related protein on human platelet activation[J]. Clin Sci（Lond），2007，113(7):319-327. DOI：10.1042/CS20070010.
[19]	WANG M W, YANG Z, CHEN X，et al. Activation of PTH1R alleviates epididymitis and orchitis through gq and β-arrestin-1 pathways[J]. Proc Natl Acad Sci USA，2021，118(45):e2107363118. DOI：10.1073/pnas.2107363118.
[20]	SUN C N, LI S L. PTHR1 in osteosarcoma：specific molecular mechanisms and comprehensive functional perspective[J]. J Cell Mol Med，2021，25(7):3175-3181. DOI：10.1111/jcmm.16420.
[21]	ESBRIT P, SANTOS S, ORTEGA A，et al. Parathyroid hormone-related protein as a renal regulating factor. From vessels to glomeruli and tubular epithelium[J]. Am J Nephrol，2001，21(3):179-184. DOI：10.1159/000046244.
[22]	IZQUIERDO A, LÓPEZ-LUNA P, ORTEGA A，et al. The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes[J]. Kidney Int，2006，69(12):2171-2177. DOI：10.1038/sj.ki.5000195.
[23]	WOLF G. New insights into the pathophysiology of diabetic nephropathy：from haemodynamics to molecular pathology[J]. Eur J Clin Invest，2004，34(12):785-796. DOI：10.1111/j.1365-2362.2004.01429.x.
[24]	ROMERO M, ORTEGA A, IZQUIERDO A，et al. Parathyroid hormone-related protein induces hypertrophy in podocytes via TGF-beta（1）and p27（Kip1）：implications for diabetic nephropathy[J]. Nephrol Dial Transplant，2010，25(8):2447-2457. DOI：10.1093/ndt/gfq104.
[25]	ROMERO M, ORTEGA A, OLEA N，et al. Novel role of parathyroid hormone-related protein in the pathophysiology of the diabetic kidney：evidence from experimental and human diabetic nephropathy[J]. J Diabetes Res，2013，2013:162846. DOI：10.1155/2013/162846.
[26]	ORTEGA A, ROMERO M, IZQUIERDO A，et al. Parathyroid hormone-related protein is a hypertrophy factor for human mesangial cells：implications for diabetic nephropathy[J]. J Cell Physiol，2012，227(5):1980-1987. DOI：10.1002/jcp.22926.
[27]	QIU T, WU X W, ZHANG F J，et al. TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling[J]. Nat Cell Biol，2010，12(3):224-234. DOI：10.1038/ncb2022.
[28]	WU S Z, YANG S J, CHEN H M，et al. Dual roles of parathyroid hormone related protein in TGF-β1 signaling and fibronectin up-regulation in mesangial cells[J]. Biosci Rep，2017，37(5):BSR20171061. DOI：10.1042/BSR20171061.
[29]	PENG F F, XIAO Z L, CHEN H M，et al. Parathyroid hormone inhibits TGF-β/Smad signaling and extracellular matrix proteins upregulation in rat mesangial cells[J]. Biochem Biophys Res Commun，2016，478(3):1093-1098. DOI：10.1016/j.bbrc.2016.08.073.
[30]	MA Y H, FANG L, ZHANG R，et al. Cyclophosphamide attenuates fibrosis in lupus nephritis by regulating mesangial cell cycle progression[J]. Dis Markers，2021，2021:3803601. DOI：10.1155/2021/3803601.
[31]	HOCHANE M, RAISON D, COQUARD C，et al. Parathyroid hormone-related protein is a mitogenic and a survival factor of mesangial cells from male mice：role of intracrine and paracrine pathways[J]. Endocrinology，2013，154(2):853-864. DOI：10.1210/en.2012-1802.
[32]	ISHAQUE A, DUNN M J, SOROKIN A. Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells[J]. J Biol Chem，2003，278(12):10629-10640. DOI：10.1074/jbc.M210559200.
[33]	HOCHANE M, RAISON D, COQUARD C，et al. Parathyroid hormone-related protein modulates inflammation in mouse mesangial cells and blunts apoptosis by enhancing COX-2 expression[J]. Am J Physiol Cell Physiol，2018，314(2):C242-253. DOI：10.1152/ajpcell.00018.2017.
[34]	HOCHANE M, RAISON D, COQUARD C，et al. Parathyroid hormone-related protein contributes to early healing of habu snake venom-induced glomerulonephritis in mice[J]. Am J Pathol，2018，188(4):863-875. DOI：10.1016/j.ajpath.2017.12.012.
[35]	LIU Y H. Cellular and molecular mechanisms of renal fibrosis[J]. Nat Rev Nephrol，2011，7(12):684-696. DOI：10.1038/nrneph.2011.149.
[36]	ARDURA J A, RAYEGO-MATEOS S, RÁMILA D，et al. Parathyroid hormone-related protein promotes epithelial-mesenchymal transition[J]. J Am Soc Nephrol，2010，21(2):237-248. DOI：10.1681/ASN.2009050462.
[37]	ARDURA J A, BERRUGUETE R, RÁMILA D，et al. Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney[J]. Am J Physiol Renal Physiol，2008，295(2):F415-425. DOI：10.1152/ajprenal.00018.2008.
[38]	CHEN H M, DAI J J, ZHU R，et al. Parathyroid hormone-related protein induces fibronectin up-regulation in rat mesangial cells through reactive oxygen species/Src/EGFR signaling[J]. Biosci Rep，2019，39(4):BSR20182293. DOI：10.1042/BSR20182293.
[39]	RÁMILA D, ARDURA J A, ESTEBAN V，et al. Parathyroid hormone-related protein promotes inflammation in the kidney with an obstructed ureter[J]. Kidney Int，2008，73(7):835-847. DOI：10.1038/sj.ki.5002775.
[40]	GRACIOLLI F G, NEVES K R, BARRETO F，et al. The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease[J]. Kidney Int，2017，91(6):1436-1446. DOI：10.1016/j.kint.2016.12.029.
[41]	IWASAKI-ISHIZUKA Y, YAMATO H, NII-KONO T，et al. Downregulation of parathyroid hormone receptor gene expression and osteoblastic dysfunction associated with skeletal resistance to parathyroid hormone in a rat model of renal failure with low turnover bone[J]. Nephrol Dial Transplant，2005，20(9):1904-1911. DOI：10.1093/ndt/gfh876.
[42]	MANDL A, BURBELO P D, DI PASQUALE G，et al. Parathyroid hormone resistance and autoantibodies to the PTH1 receptor[J]. N Engl J Med，2021，385(21):1974-1980. DOI：10.1056/NEJMoa2109409.
[43]	LIU F, FU P, FAN W X，et al. Involvement of parathyroid hormone-related protein in vascular calcification of chronic haemodialysis patients[J]. Nephrology（Carlton），2012，17(6):552-560. DOI：10.1111/j.1440-1797.2012.01601.x.
[44]	CARRILLO-LÓPEZ N, MARTÍNEZ-ARIAS L, ALONSO-MONTES C，et al. The receptor activator of nuclear factor κΒ ligand receptor leucine-rich repeat-containing G-protein-coupled receptor 4 contributes to parathyroid hormone-induced vascular calcification[J]. Nephrol Dial Transplant，2021，36(4):618-631. DOI：10.1093/ndt/gfaa290.
[45]	KIR S, KOMABA H, GARCIA A P，et al. PTH/PTHrP receptor mediates Cachexia in models of kidney failure and cancer[J]. Cell Metab，2016，23(2):315-323. DOI：10.1016/j.cmet.2015.11.003.
[46]	PEFANIS A, IERINO F L, MURPHY J M，et al. Regulated necrosis in kidney ischemia-reperfusion injury[J]. Kidney Int，2019，96(2):291-301. DOI：10.1016/j.kint.2019.02.009.
[47]	SANTOS S, BOSCH R J, ORTEGA A，et al. Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure[J]. Kidney Int，2001，60(3):982-995. DOI：10.1046/j.1523-1755.2001.060003982.x.
[48]	ARDURA J A, SANZ A B, ORTIZ A，et al. Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2[J]. Kidney Int，2013，83(5):825-834. DOI：10.1038/ki.2012.476.
[49]	FIASCHI-TAESCH N M, SANTOS S, REDDY V，et al. Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice：the efficacy of parathyroid hormone-related protein and hepatocyte growth factor[J]. J Am Soc Nephrol，2004，15(1):112-125. DOI：10.1097/01.asn.0000102470.12285.c6.
[50]	ORTEGA A, RÁMILA D, ARDURA J A，et al. Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity[J]. J Am Soc Nephrol，2006，17(6):1594-1603. DOI：10.1681/ASN.2005070690.
[51]	ORTEGA A, OLEA-HERRERO N, ARENAS M I，et al. Urinary excretion of parathyroid hormone-related protein correlates with renal function in control rats and rats with cisplatin nephrotoxicity[J]. Am J Physiol Renal Physiol，2019，317(4):F874-880. DOI：10.1152/ajprenal.00091.2019.