Bartter/Gitelman综合征患者临床病理分析及其肾脏致密斑COX-2表达
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摘要
背景
Bartter综合征(BS)和Gitelman综合征(GS)是一类遗传性失盐型肾小管疾病(salt-losing tubulopathies,SLTs),两者致病基因不同,病理生理也不尽相同,鉴别需基因诊断。GS的基因突变类型和临床表现有很大的异质性。已证实在BS患者的肾脏球旁器致密斑有环氧化酶-2(COX-2)蛋白和mRNA表达,认为BS患者的肾素增加至少部分由COX-2激活导致,关于致密斑中COX-2的活化在GS病理生理改变中的作用不得而知。
目的
总结遗传性SLTs患者临床表现、病理特点；探讨中国人GS基因突变类型及其与临床表型的相关性,了解GS患者的肾脏致密斑COX-2的表达情况在肾素-血管紧张素系统(RAS)活化中的作用。
方法
入选标准：2000年12月～2009年6月在北京协和医院住院,临床诊断为Bartter综合征或Gitelman综合征的病人共36例。诊断标准如下：临床诊断符合低钾性碱中毒、肾性失盐、肾素、血管紧张素-Ⅱ、醛固酮水平增高、正常血压、伴或不伴低镁血症和低尿钙；排除继发因素如甲亢、结缔组织病、服用利尿剂、缓泻剂等药物、神经性厌食症等。对留有外周静脉血的11例病人进行SLC12A3基因全部26个外显子扩增,直接测序后与正常序列比对,查找突变,并分析基因型与表型关系；对留有肾脏病理穿刺标本的19例病人进行肾脏球旁器肾素和COX-2蛋白的检测,对照组选择血压正常、肾小球病理诊断为轻微病变的患者共5例。
结果
1、9/11例患者发现SLC12A3基因上的变异,包括2例纯合突变,3例复合杂合突变,4例单杂合突变。共发现7个错义突变,2个移码突变,其中6个错义突变、1个插入突变为已经报道的突变；新发现1种错义突变和1个缺失突变。单纯杂合子与复合杂合子／纯合子患者相比,一般情况、生化检查等均无明显差异；
2、此类遗传性失盐性肾小管疾病最常见症状为肢体乏力(94%)、心悸、胸闷(56%)、肢体抽搐(47%)、肢体麻木(42%)；血镁与尿钙有很好的正相关性；24小时尿钾、尿氯有明显的性别差异(p<0.05),男性高于女性；多数患者有RAS激活,以血管紧张素Ⅱ最为明显。亚临床甲状腺机能减退和糖耐量异常者比例分别为31%(9/29)和30%(8/27)。35例患者中的13例入院时心电图表现T波低平或有u波。
3、所有的病例最突出的肾脏病理表现为肾小球球外系膜区增宽、球旁细胞增生,检出率高达92%(22/24)。92%(22/24)的患者球旁器以外的肾脏组织病变较轻,最常见改变为肾小管上皮细胞变性,绝大部分表现为空泡变性,个别表现为颗粒、浊肿变性；慢性化表现如灶性间质纤维化、炎症细胞浸润者也较多,但程度较轻。
4、19例患者和5例对照者肾脏球旁器均检测到肾素表达,表达集中于入球动脉,患者组明显高于后者,两者相比有显著差异(p<0.001)。19例患者中有18例在致密斑中成功检出COX-2蛋白表达,5例对照组均未检出,患者阳性致密斑与肾小球个数比平均为26%(0-67%),两者相比有显著差异(p<0.001)。
结论
1、在遗传性失盐性肾小管疾病中,Gitelman综合征发病率可能并不低；
2、低钾相关症状是遗传性失盐性肾小管疾病的主要临床表现,在此类疾病中,血镁、尿钙有正相关性；
3、遗传性失盐性肾小管疾病患者中90%以上可见到球旁器增生,肾脏局部肾素表达增加与全身RAS活化密切相关；
4、Gitelman综合征患者肾脏球旁器致密斑COX-2表达可能参与局部RAS活化。
Background
Bartter syndrome(BS) and Gitelman syndrome(GS) are similar hereditary hypokalaemic salt-losing tubulopathies(SLTs). They have different pathogenic gene. The gene detective is needed to confirm the diagnosis. COX-2protein and mRNA expression has been observed in the macula densa (MD) cells in patients with BS.But weather COX-2involved in the activation of rennin-angiotensin systerm (RAS) of GS is still unknown, although the PGE2level of urine in these patients was normal.
Objective
The purpose of this study was to to identify the mutations of SLC12A3gene in Gitelman syndrome patients, to observe the relationship between the renin/COX-2expression of Juxtaglomerular apparatus (JGA) and the plasm renin activity(PRA) of SLTs patients.
Methods
Clinical data of36patients who hospitalized in Peking Union Medical College Hospital (PUMCH) with hereditary hypokalaemic SLTs were collected and analyzed. SLC12A3gene of11patients from9unrelated families (3femals from one family, two generations) were analyzed by direct sequencing. The clinical features and genotype of heterozygous and compound heterozygous/homozygous were compared. The PRA, Angll, aldosterone were measured by RI. The kidney biopsy were done in24patients,5of them were confirmed as GS by gene detective. Renin and COX-2protein expression of the Juxtaglomerular apparatus(JGA) were measured by immunohistochemistry. The control group was5patients with minimal change of the kidney pathology and without hypertension.
Results
1. Eight mutations of SLC12A3gene were identified in9patients. Two were novel variants, including one missense mutations:Asn534Lys; one deletion:493～496delACGG. Eight were recurrent mutations:Thr60Met、Thr304Met, Arg399Cys, Cys430Gly,Asp486Asn,Ser615Leu and810insATTGGCGTGGTCTCGGTC. The homozygous or heterozygous mutation Thr60Met was found in2of9patients. There were no obviously differences of chinical features and chemical examination between simple heterozygous and compound heterozygous/homozygous.
2. The common symptoms were limbs fatigue (94%), palpitations or chest tightness (56%), tetany (47%), limb numbness (42%). Plasma renin concentration and Ang II was obviously increased in these patients. Plasm magnesium and urinary calcium concentration have a good positive correlation. There was no gender differences of chemical examinations except urinary potassium and chlorides.1/3patients were companied with the subclinical hypothyroidism (31%) or impaired glucose tolerance (30%). Abnormal ECG changes were observed in13cases.
3. Juxtaglomerular apparatus hyperplasia was observed in most of the hereditary hypokalaemic SLTs patients (92%). Vacuolar degeneration of the renal epithelial tubular cells was common. In some cases, chronic index such as focal interstitial fibrosis, inflammatory cell infiltration were also observed.
4. Renin expression in JG cells and COX-2expression in MD cells were obviously higher in the hereditary hypokalaemic SLTs patients (including5Gitelman syndrome patients) than control, which have good relationship with the PRA plasm Ang II.
Conclusion
1. The incidence of Gitelman syndrome may be higher than expected. Gene analysis is essential to diagnose Gitelman syndrome.
2. Hypokalaemia-related symptoms are the most prominent clinical manifestations of hereditary hypokalaemic SLTs. In these patients, plasma magnesium and urinary calcium have a good positive correlation.
3. The JGA hyperplasia was observed in more than90%of these patients, which have good relationship with the PRA and plasma Ang Ⅱ.
4. The COX-2expression in MD cells may be involved in the RAS activation in GS patients.
Bartter综合征(BS)和Gitelman综合征(GS)是一类遗传性失盐型肾小管疾病(salt-losing tubulopathies,SLTs),两者致病基因不同,病理生理也不尽相同,鉴别需基因诊断。GS的基因突变类型和临床表现有很大的异质性。已证实在BS患者的肾脏球旁器致密斑有环氧化酶-2(COX-2)蛋白和mRNA表达,认为BS患者的肾素增加至少部分由COX-2激活导致,关于致密斑中COX-2的活化在GS病理生理改变中的作用不得而知。
目的
总结遗传性SLTs患者临床表现、病理特点；探讨中国人GS基因突变类型及其与临床表型的相关性,了解GS患者的肾脏致密斑COX-2的表达情况在肾素-血管紧张素系统(RAS)活化中的作用。
方法
入选标准：2000年12月～2009年6月在北京协和医院住院,临床诊断为Bartter综合征或Gitelman综合征的病人共36例。诊断标准如下：临床诊断符合低钾性碱中毒、肾性失盐、肾素、血管紧张素-Ⅱ、醛固酮水平增高、正常血压、伴或不伴低镁血症和低尿钙；排除继发因素如甲亢、结缔组织病、服用利尿剂、缓泻剂等药物、神经性厌食症等。对留有外周静脉血的11例病人进行SLC12A3基因全部26个外显子扩增,直接测序后与正常序列比对,查找突变,并分析基因型与表型关系；对留有肾脏病理穿刺标本的19例病人进行肾脏球旁器肾素和COX-2蛋白的检测,对照组选择血压正常、肾小球病理诊断为轻微病变的患者共5例。
结果
1、9/11例患者发现SLC12A3基因上的变异,包括2例纯合突变,3例复合杂合突变,4例单杂合突变。共发现7个错义突变,2个移码突变,其中6个错义突变、1个插入突变为已经报道的突变；新发现1种错义突变和1个缺失突变。单纯杂合子与复合杂合子／纯合子患者相比,一般情况、生化检查等均无明显差异；
2、此类遗传性失盐性肾小管疾病最常见症状为肢体乏力(94%)、心悸、胸闷(56%)、肢体抽搐(47%)、肢体麻木(42%)；血镁与尿钙有很好的正相关性；24小时尿钾、尿氯有明显的性别差异(p<0.05),男性高于女性；多数患者有RAS激活,以血管紧张素Ⅱ最为明显。亚临床甲状腺机能减退和糖耐量异常者比例分别为31%(9/29)和30%(8/27)。35例患者中的13例入院时心电图表现T波低平或有u波。
3、所有的病例最突出的肾脏病理表现为肾小球球外系膜区增宽、球旁细胞增生,检出率高达92%(22/24)。92%(22/24)的患者球旁器以外的肾脏组织病变较轻,最常见改变为肾小管上皮细胞变性,绝大部分表现为空泡变性,个别表现为颗粒、浊肿变性；慢性化表现如灶性间质纤维化、炎症细胞浸润者也较多,但程度较轻。
4、19例患者和5例对照者肾脏球旁器均检测到肾素表达,表达集中于入球动脉,患者组明显高于后者,两者相比有显著差异(p<0.001)。19例患者中有18例在致密斑中成功检出COX-2蛋白表达,5例对照组均未检出,患者阳性致密斑与肾小球个数比平均为26%(0-67%),两者相比有显著差异(p<0.001)。
结论
1、在遗传性失盐性肾小管疾病中,Gitelman综合征发病率可能并不低；
2、低钾相关症状是遗传性失盐性肾小管疾病的主要临床表现,在此类疾病中,血镁、尿钙有正相关性；
3、遗传性失盐性肾小管疾病患者中90%以上可见到球旁器增生,肾脏局部肾素表达增加与全身RAS活化密切相关；
4、Gitelman综合征患者肾脏球旁器致密斑COX-2表达可能参与局部RAS活化。
Background
Bartter syndrome(BS) and Gitelman syndrome(GS) are similar hereditary hypokalaemic salt-losing tubulopathies(SLTs). They have different pathogenic gene. The gene detective is needed to confirm the diagnosis. COX-2protein and mRNA expression has been observed in the macula densa (MD) cells in patients with BS.But weather COX-2involved in the activation of rennin-angiotensin systerm (RAS) of GS is still unknown, although the PGE2level of urine in these patients was normal.
Objective
The purpose of this study was to to identify the mutations of SLC12A3gene in Gitelman syndrome patients, to observe the relationship between the renin/COX-2expression of Juxtaglomerular apparatus (JGA) and the plasm renin activity(PRA) of SLTs patients.
Methods
Clinical data of36patients who hospitalized in Peking Union Medical College Hospital (PUMCH) with hereditary hypokalaemic SLTs were collected and analyzed. SLC12A3gene of11patients from9unrelated families (3femals from one family, two generations) were analyzed by direct sequencing. The clinical features and genotype of heterozygous and compound heterozygous/homozygous were compared. The PRA, Angll, aldosterone were measured by RI. The kidney biopsy were done in24patients,5of them were confirmed as GS by gene detective. Renin and COX-2protein expression of the Juxtaglomerular apparatus(JGA) were measured by immunohistochemistry. The control group was5patients with minimal change of the kidney pathology and without hypertension.
Results
1. Eight mutations of SLC12A3gene were identified in9patients. Two were novel variants, including one missense mutations:Asn534Lys; one deletion:493～496delACGG. Eight were recurrent mutations:Thr60Met、Thr304Met, Arg399Cys, Cys430Gly,Asp486Asn,Ser615Leu and810insATTGGCGTGGTCTCGGTC. The homozygous or heterozygous mutation Thr60Met was found in2of9patients. There were no obviously differences of chinical features and chemical examination between simple heterozygous and compound heterozygous/homozygous.
2. The common symptoms were limbs fatigue (94%), palpitations or chest tightness (56%), tetany (47%), limb numbness (42%). Plasma renin concentration and Ang II was obviously increased in these patients. Plasm magnesium and urinary calcium concentration have a good positive correlation. There was no gender differences of chemical examinations except urinary potassium and chlorides.1/3patients were companied with the subclinical hypothyroidism (31%) or impaired glucose tolerance (30%). Abnormal ECG changes were observed in13cases.
3. Juxtaglomerular apparatus hyperplasia was observed in most of the hereditary hypokalaemic SLTs patients (92%). Vacuolar degeneration of the renal epithelial tubular cells was common. In some cases, chronic index such as focal interstitial fibrosis, inflammatory cell infiltration were also observed.
4. Renin expression in JG cells and COX-2expression in MD cells were obviously higher in the hereditary hypokalaemic SLTs patients (including5Gitelman syndrome patients) than control, which have good relationship with the PRA plasm Ang II.
Conclusion
1. The incidence of Gitelman syndrome may be higher than expected. Gene analysis is essential to diagnose Gitelman syndrome.
2. Hypokalaemia-related symptoms are the most prominent clinical manifestations of hereditary hypokalaemic SLTs. In these patients, plasma magnesium and urinary calcium have a good positive correlation.
3. The JGA hyperplasia was observed in more than90%of these patients, which have good relationship with the PRA and plasma Ang Ⅱ.
4. The COX-2expression in MD cells may be involved in the RAS activation in GS patients.
引文
1. Reinalter, S.C., et al., Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int,2002.62(1):p.253-60.
2. Bartter, F.C., et al., Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med, 1962.33:p.811-28.
3. Gitelman, H.J., J.B. Graham, and L.G Welt, A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians, 1966.79:p.221-35.
4. Simon, D.B., et al., Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type Ⅲ. Nat Genet,1997.17(2):p.171-8.
5. Simon, D.B., et al., Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet,1996.12(1):p.24-30.
6. Harris, R.C., et al., Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest,1994.94(6):p.2504-10.
7. Komhoff, M., et al., Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int,2000.58(6):p. 2420-4.
8. Kleta, R., C. Basoglu, and E. Kuwertz-Broking, New treatment options for Bartter's syndrome. N Engl J Med,2000.343(9):p.661-2.
9. Luthy, C., et al., Normal prostaglandinuria E2 in Gitelman's syndrome, the hypocalciuric variant of Bartter's syndrome. Am J Kidney Dis,1995.25(6):p. 824-8.
10. Hamberg, M. and B. Samuelsson, On the metabolism of prostaglandins E 1 and E 2 in man. J Biol Chem,1971.246(22):p.6713-21.
11. Simon, D.B., et al., Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet,1996.13(2):p.183-8.
12. Austin, H.A.,3rd, et al., Diffuse proliferative lupus nephritis:identification of specific pathologic features affecting renal outcome. Kidney Int,1984.25(4):p. 689-95.
13. Sutton, R.A., et al., Bartter's syndrome:evidence suggesting a distal tubular defect in a hypocalciuric variant of the syndrome. Miner Electrolyte Metab,1992. 18(1):p.43-51.
14. Bettinelli, A., et al., Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis:Bartter and Gitelman syndromes. J Pediatr,1992.120(1):p.38-43.
15. Zelikovic, L, et al., A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int,2003.63(1):p.24-32.
16. Yoo, T.H., et al., Identification of novel mutations in Na-Cl cotransporter gene in a Korean patient with atypical Gitelman's syndrome. Am J Kidney Dis,2003. 42(6):p. El 1-6.
17. Maki, N., et al., Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant,2004.19(7):p.1761-6.
18. Qin, L., et al., Identification of five novel variants, in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome. Nephrology (Carlton),2009.14(1):p.52-8.
19. Lemmink, H.H., et al., Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int,1998.54(3):p.720-30.
20. Riveira-Munoz, E., et al., Gitelman's syndrome:towards genotype-phenotype correlations? Pediatr Nephrol,2007.22(3):p.326-32.
21. Hashida, T., et al., Loss of consciousness and hypokalemia in an elderly man with a mutation of the thiazide-sensitive Na-Cl cotransporter gene. Endocr J,2006. 53(6):p.859-63.
22. Tago, N., et al., A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res,2004.27(5):p.327-31.
23. Coto, E., et al., A new mutation (intron 9+1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int,2004.65(1):p.25-9.
24. Verlander, J.W., et al., Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest,1998.101(8):p.1661-9.
25. Chen, Z., D.A. Vaughn, and D.D. Fanestil, Influence of gender on renal thiazide diuretic receptor density and response. J Am Soc Nephrol,1994.5(4):p.1112-9.
26. Kunchaparty, S., et al., Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome. Am J Physiol,1999. 277(4 Pt 2):p. F643-9.
27. Pachulski, R.T., F. Lopez, and R. Sharaf, Gitelman's not-so-benign syndrome. N Engl J Med,2005.353(8):p.850-1.
28. Cortesi, C., et al., Prevention of cardiac arrhythmias in pediatric patients with normotensive-hypokalemic tubulopathy. Current attitude among European pediatricians. Pediatr Nephrol,2003.18(8):p.729-30.
29. Bettinelli, A., et al., Electrocardiogram with prolonged QT interval in Gitelman disease. Kidney Int,2002.62(2):p.580-4.
30. Davis, P.A., et al., Insulin signaling, glucose metabolism, and the angiotensin Ⅱ signaling system:studies in Bartter's/Gitelman's syndromes. Diabetes Care,2006. 29(2):p.469-71.
31. Tikellis, C, et al., Improved islet morphology after blockade of the renin-angiotensin system in the ZDFrat. Diabetes,2004.53(4):p.989-97.
32. Taniyama, Y., et al., Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin Ⅱ. Arterioscler Thromb Vase Biol,2005.25(6):p.1142-7.
33. Lindholm, L.H., et al., Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens,2002.20(9):p. 1879-86.
34. Klahr, S. and J. Morrissey, Angiotensin Ⅱ and gene expression in the kidney. Am J Kidney Dis,1998.31(1):p.171-6.
35. Salomonsson, M., et al., Chloride concentration in macula densa and cortical thick ascending limb cells. Kidney Int Suppl,1991.32:p. S51-4.
36. Friis, U.G., et al., Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells. Am J Physiol Renal Physiol,2005.289(5):p. F989-97.
37. Harris, R.C. and M.D. Breyer, Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol,2001.281(1):p. F1-11.
38. Khan, K.N., et al., Interspecies differences in renal localization of cyclooxygenase isoforms:implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol,1998.26(5):p.612-20.
39. Stichtenoth, D.O., B. Wagner, and J.C. Frolich, Effect of selective inhibition of the inducible cyclooxygenase on renin release in healthy volunteers. J Investig Med, 1998.46(6):p.290-6.
40. Nusing, R.M. and H.W. Seyberth, The role of cyclooxygenases and prostanoid receptorsin furosemide-like salt losing tubulopathy:the hyperprostaglandin E syndrome. Acta Physiol Scand,2004.181(4):p.523-8.
41. Carmine, Z., et al., The renal tubular defect of Banter's syndrome. Nephron,1982. 32(2):p.140-8.
1. Bartter, F.C., et al., Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med, 1962.33:p.811-28.
2. Scheinman, S.J., et al., Genetic disorders of renal electrolyte transport. N Engl J Med,1999.340(15):p.1177-87.
3. Gitelman, H.J., J.B. Graham, and L.G. Welt, A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians, 1966.79:p.221-35.
4. Landau, D., et al., Infantile variant of Bartter syndrome and sensorineural deafness:a new autosomal recessive disorder. Am J Med Genet,1995.59(4):p. 454-9.
5. Simon, D.B., et al., Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet,1996.13(2):p.183-8.
6. Simon, D.B., et al., Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet,1996.14(2):p.152-6.
7. Simon, D.B., et al., Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type Ⅲ. Nat Genet,1997.17(2):p.171-8.
8. Birkenhager, R., et al., Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet,2001.29(3):p.310-4.
9. Watanabe, S., et al., Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet,2002.360(9334):p.692-4.
10. Simon, D.B., et al., Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet,1996.12(1):p.24-30.
11. Reissinger, A., et al., Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res,2002.25(6):p.354-62.
12. Tago, N., et al., A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res,2004.27(5):p.327-31.
13. 刘冬梅,曾正培.成人Bartter综合征14例临床分析。临床内科杂志,2003,20(1)：38-39.
14. 邵乐平,任红,王伟铭,等.Gitelman综合征SLC12A3基因突变研究.中华肾 脏病杂志,2007,23(6)：351-356.
15. Agarwal, R., et al., Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int,2005.68(6):p.2823-8.
16. Coto, E., et al., A new mutation (intron 9+1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int,2004.65(1):p.25-9.
17. Hoover, R.S., et al., N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter. J Am Soc Nephrol,2003.14(2):p.271-82.
18. Kunchaparty, S., et al., Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome. Am J Physiol,1999. 277(4 Pt 2):p. F643-9.
19. De Jong, J.C., et al., Functional expression of mutations in the human NaCl cotransporter:evidence for impaired routing mechanisms in Gitelman's syndrome. J Am Soc Nephrol,2002.13(6):p.1442-8.
20. Verlander, J.W., et al., Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest,1998.101(8):p.1661-9.
21. Chen, Z., D.A. Vaughn, and D.D. Fanestil, Influence of gender on renal thiazide diuretic receptor density and response. J Am Soc Nephrol,1994.5(4):p.1112-9.
22. Jeck, N., et al., Salt handling in the distal nephron:lessons learned from inherited human disorders. Am J Physiol Regul Integr Comp Physiol,2005.288(4):p. R782-95.
23. Lemmink, H.H., et al., Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int,1998.54(3):p.720-30.
24. Hashida, T., et al., Loss of consciousness and hypokalemia in an elderly man with a mutation of the thiazide-sensitive Na-Cl cotransporter gene. Endocr J,2006. 53(6):p.859-63.
25. Fava, C., et al., Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet, 2008.17(3):p.413-8.
26. Riveira-Munoz, E., et al., Gitelman's syndrome:towards genotype-phenotype correlations? Pediatr Nephrol,2007.22(3):p.326-32.
27. Bonfante, L., et al., Chronic renal failure, end-stage renal disease, and peritoneal dialysis in Gitelman's syndrome. Am J Kidney Dis,2001.38(1):p.165-8.
28. Calo, L.A., et al., Kidney transplant in Gitelman's syndrome. Report of the first case. J Nephrol,2003.16(1):p.144-7.
29. Cruz, D.N., et al., Gitelman's syndrome revisited:an evaluation of symptoms and health-related quality of life. Kidney Int,2001.59(2):p.710-7.
30. Pachulski, R.T., F. Lopez, and R. Sharaf, Gitelman's not-so-benign syndrome. N Engl J Med,2005.353(8):p.850-1.
31. Cortesi, C., et al., Prevention of cardiac arrhythmias in pediatric patients with normotensive-hypokalemic tubulopathy. Current attitude among European pediatricians. Pediatr Nephrol,2003.18(8):p.729-30.
32. Foglia, P.E., et al., Cardiac work up in primary renal hypokalaemia-hypomagnesaemia (Gitelman syndrome). Nephrol Dial Transplant, 2004.19(6):p.1398-402.
33. Bettinelli, A., et al., Electrocardiogram with prolonged QT interval in Gitelman disease. Kidney Int,2002.62(2):p.580-4.
34. Schweda, F. and A. Kurtz, Cellular mechanism of renin release. Acta Physiol Scand,2004.181(4):p.383-90.
35. Chen, L., et al., Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsalpha in juxtaglomerular cells. Am J Physiol Renal Physiol,2007.292(1):p. F27-37.
36. Komhoff, M., et al., Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int,2000.58(6):p. 2420-4.
37. Kleta, R., C. Basoglu, and E. Kuwertz-Broking, New treatment options for Bartter's syndrome. N Engl J Med,2000.343(9):p.661-2.
38. Nusing, R.M. and H.W. Seyberth, The role of cyclooxygenases and prostanoid receptorsin furosemide-like salt losing tubulopathy:the hyperprostaglandin E syndrome. Acta Physiol Scand,2004.181(4):p.523-8.
39. Carmine, Z., et al., The renal tubular defect of Bartter's syndrome. Nephron,1982. 32(2):p.140-8.
2. Bartter, F.C., et al., Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med, 1962.33:p.811-28.
3. Gitelman, H.J., J.B. Graham, and L.G Welt, A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians, 1966.79:p.221-35.
4. Simon, D.B., et al., Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type Ⅲ. Nat Genet,1997.17(2):p.171-8.
5. Simon, D.B., et al., Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet,1996.12(1):p.24-30.
6. Harris, R.C., et al., Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest,1994.94(6):p.2504-10.
7. Komhoff, M., et al., Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int,2000.58(6):p. 2420-4.
8. Kleta, R., C. Basoglu, and E. Kuwertz-Broking, New treatment options for Bartter's syndrome. N Engl J Med,2000.343(9):p.661-2.
9. Luthy, C., et al., Normal prostaglandinuria E2 in Gitelman's syndrome, the hypocalciuric variant of Bartter's syndrome. Am J Kidney Dis,1995.25(6):p. 824-8.
10. Hamberg, M. and B. Samuelsson, On the metabolism of prostaglandins E 1 and E 2 in man. J Biol Chem,1971.246(22):p.6713-21.
11. Simon, D.B., et al., Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet,1996.13(2):p.183-8.
12. Austin, H.A.,3rd, et al., Diffuse proliferative lupus nephritis:identification of specific pathologic features affecting renal outcome. Kidney Int,1984.25(4):p. 689-95.
13. Sutton, R.A., et al., Bartter's syndrome:evidence suggesting a distal tubular defect in a hypocalciuric variant of the syndrome. Miner Electrolyte Metab,1992. 18(1):p.43-51.
14. Bettinelli, A., et al., Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis:Bartter and Gitelman syndromes. J Pediatr,1992.120(1):p.38-43.
15. Zelikovic, L, et al., A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int,2003.63(1):p.24-32.
16. Yoo, T.H., et al., Identification of novel mutations in Na-Cl cotransporter gene in a Korean patient with atypical Gitelman's syndrome. Am J Kidney Dis,2003. 42(6):p. El 1-6.
17. Maki, N., et al., Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant,2004.19(7):p.1761-6.
18. Qin, L., et al., Identification of five novel variants, in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome. Nephrology (Carlton),2009.14(1):p.52-8.
19. Lemmink, H.H., et al., Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int,1998.54(3):p.720-30.
20. Riveira-Munoz, E., et al., Gitelman's syndrome:towards genotype-phenotype correlations? Pediatr Nephrol,2007.22(3):p.326-32.
21. Hashida, T., et al., Loss of consciousness and hypokalemia in an elderly man with a mutation of the thiazide-sensitive Na-Cl cotransporter gene. Endocr J,2006. 53(6):p.859-63.
22. Tago, N., et al., A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res,2004.27(5):p.327-31.
23. Coto, E., et al., A new mutation (intron 9+1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int,2004.65(1):p.25-9.
24. Verlander, J.W., et al., Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest,1998.101(8):p.1661-9.
25. Chen, Z., D.A. Vaughn, and D.D. Fanestil, Influence of gender on renal thiazide diuretic receptor density and response. J Am Soc Nephrol,1994.5(4):p.1112-9.
26. Kunchaparty, S., et al., Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome. Am J Physiol,1999. 277(4 Pt 2):p. F643-9.
27. Pachulski, R.T., F. Lopez, and R. Sharaf, Gitelman's not-so-benign syndrome. N Engl J Med,2005.353(8):p.850-1.
28. Cortesi, C., et al., Prevention of cardiac arrhythmias in pediatric patients with normotensive-hypokalemic tubulopathy. Current attitude among European pediatricians. Pediatr Nephrol,2003.18(8):p.729-30.
29. Bettinelli, A., et al., Electrocardiogram with prolonged QT interval in Gitelman disease. Kidney Int,2002.62(2):p.580-4.
30. Davis, P.A., et al., Insulin signaling, glucose metabolism, and the angiotensin Ⅱ signaling system:studies in Bartter's/Gitelman's syndromes. Diabetes Care,2006. 29(2):p.469-71.
31. Tikellis, C, et al., Improved islet morphology after blockade of the renin-angiotensin system in the ZDFrat. Diabetes,2004.53(4):p.989-97.
32. Taniyama, Y., et al., Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin Ⅱ. Arterioscler Thromb Vase Biol,2005.25(6):p.1142-7.
33. Lindholm, L.H., et al., Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens,2002.20(9):p. 1879-86.
34. Klahr, S. and J. Morrissey, Angiotensin Ⅱ and gene expression in the kidney. Am J Kidney Dis,1998.31(1):p.171-6.
35. Salomonsson, M., et al., Chloride concentration in macula densa and cortical thick ascending limb cells. Kidney Int Suppl,1991.32:p. S51-4.
36. Friis, U.G., et al., Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells. Am J Physiol Renal Physiol,2005.289(5):p. F989-97.
37. Harris, R.C. and M.D. Breyer, Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol,2001.281(1):p. F1-11.
38. Khan, K.N., et al., Interspecies differences in renal localization of cyclooxygenase isoforms:implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol,1998.26(5):p.612-20.
39. Stichtenoth, D.O., B. Wagner, and J.C. Frolich, Effect of selective inhibition of the inducible cyclooxygenase on renin release in healthy volunteers. J Investig Med, 1998.46(6):p.290-6.
40. Nusing, R.M. and H.W. Seyberth, The role of cyclooxygenases and prostanoid receptorsin furosemide-like salt losing tubulopathy:the hyperprostaglandin E syndrome. Acta Physiol Scand,2004.181(4):p.523-8.
41. Carmine, Z., et al., The renal tubular defect of Banter's syndrome. Nephron,1982. 32(2):p.140-8.
1. Bartter, F.C., et al., Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med, 1962.33:p.811-28.
2. Scheinman, S.J., et al., Genetic disorders of renal electrolyte transport. N Engl J Med,1999.340(15):p.1177-87.
3. Gitelman, H.J., J.B. Graham, and L.G. Welt, A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians, 1966.79:p.221-35.
4. Landau, D., et al., Infantile variant of Bartter syndrome and sensorineural deafness:a new autosomal recessive disorder. Am J Med Genet,1995.59(4):p. 454-9.
5. Simon, D.B., et al., Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet,1996.13(2):p.183-8.
6. Simon, D.B., et al., Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet,1996.14(2):p.152-6.
7. Simon, D.B., et al., Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type Ⅲ. Nat Genet,1997.17(2):p.171-8.
8. Birkenhager, R., et al., Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet,2001.29(3):p.310-4.
9. Watanabe, S., et al., Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet,2002.360(9334):p.692-4.
10. Simon, D.B., et al., Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet,1996.12(1):p.24-30.
11. Reissinger, A., et al., Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res,2002.25(6):p.354-62.
12. Tago, N., et al., A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res,2004.27(5):p.327-31.
13. 刘冬梅,曾正培.成人Bartter综合征14例临床分析。临床内科杂志,2003,20(1)：38-39.
14. 邵乐平,任红,王伟铭,等.Gitelman综合征SLC12A3基因突变研究.中华肾 脏病杂志,2007,23(6)：351-356.
15. Agarwal, R., et al., Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int,2005.68(6):p.2823-8.
16. Coto, E., et al., A new mutation (intron 9+1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int,2004.65(1):p.25-9.
17. Hoover, R.S., et al., N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter. J Am Soc Nephrol,2003.14(2):p.271-82.
18. Kunchaparty, S., et al., Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome. Am J Physiol,1999. 277(4 Pt 2):p. F643-9.
19. De Jong, J.C., et al., Functional expression of mutations in the human NaCl cotransporter:evidence for impaired routing mechanisms in Gitelman's syndrome. J Am Soc Nephrol,2002.13(6):p.1442-8.
20. Verlander, J.W., et al., Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest,1998.101(8):p.1661-9.
21. Chen, Z., D.A. Vaughn, and D.D. Fanestil, Influence of gender on renal thiazide diuretic receptor density and response. J Am Soc Nephrol,1994.5(4):p.1112-9.
22. Jeck, N., et al., Salt handling in the distal nephron:lessons learned from inherited human disorders. Am J Physiol Regul Integr Comp Physiol,2005.288(4):p. R782-95.
23. Lemmink, H.H., et al., Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int,1998.54(3):p.720-30.
24. Hashida, T., et al., Loss of consciousness and hypokalemia in an elderly man with a mutation of the thiazide-sensitive Na-Cl cotransporter gene. Endocr J,2006. 53(6):p.859-63.
25. Fava, C., et al., Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet, 2008.17(3):p.413-8.
26. Riveira-Munoz, E., et al., Gitelman's syndrome:towards genotype-phenotype correlations? Pediatr Nephrol,2007.22(3):p.326-32.
27. Bonfante, L., et al., Chronic renal failure, end-stage renal disease, and peritoneal dialysis in Gitelman's syndrome. Am J Kidney Dis,2001.38(1):p.165-8.
28. Calo, L.A., et al., Kidney transplant in Gitelman's syndrome. Report of the first case. J Nephrol,2003.16(1):p.144-7.
29. Cruz, D.N., et al., Gitelman's syndrome revisited:an evaluation of symptoms and health-related quality of life. Kidney Int,2001.59(2):p.710-7.
30. Pachulski, R.T., F. Lopez, and R. Sharaf, Gitelman's not-so-benign syndrome. N Engl J Med,2005.353(8):p.850-1.
31. Cortesi, C., et al., Prevention of cardiac arrhythmias in pediatric patients with normotensive-hypokalemic tubulopathy. Current attitude among European pediatricians. Pediatr Nephrol,2003.18(8):p.729-30.
32. Foglia, P.E., et al., Cardiac work up in primary renal hypokalaemia-hypomagnesaemia (Gitelman syndrome). Nephrol Dial Transplant, 2004.19(6):p.1398-402.
33. Bettinelli, A., et al., Electrocardiogram with prolonged QT interval in Gitelman disease. Kidney Int,2002.62(2):p.580-4.
34. Schweda, F. and A. Kurtz, Cellular mechanism of renin release. Acta Physiol Scand,2004.181(4):p.383-90.
35. Chen, L., et al., Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsalpha in juxtaglomerular cells. Am J Physiol Renal Physiol,2007.292(1):p. F27-37.
36. Komhoff, M., et al., Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int,2000.58(6):p. 2420-4.
37. Kleta, R., C. Basoglu, and E. Kuwertz-Broking, New treatment options for Bartter's syndrome. N Engl J Med,2000.343(9):p.661-2.
38. Nusing, R.M. and H.W. Seyberth, The role of cyclooxygenases and prostanoid receptorsin furosemide-like salt losing tubulopathy:the hyperprostaglandin E syndrome. Acta Physiol Scand,2004.181(4):p.523-8.
39. Carmine, Z., et al., The renal tubular defect of Bartter's syndrome. Nephron,1982. 32(2):p.140-8.