Progress of pendrin in airway epithelia / 国际儿科学杂志

Pendrin is an electroneutral anion exchanger transporter, residing in the apical region of airway epithelium cells.It is responsible for the reabsorption of chloride(Cl -) and the exchange of bicarbonate(HCO 3－)or thiocyanate(SCN -) to the lumen.It is mainly involved in regulating the pH and thickness of airway surface liquid(ASL), mucin secretion, and airway defense, which is of great significance for maintaining the stability of the airway surface microenvironment.The expression of pendrin is significantly up-regulated in bronchial asthma, which is closely related to the pathological processes of the lung in bronchial asthma, such as airway hyperresponsiveness, neutrophil infiltration, and increased mucin secretion.Inhibiting the function of pendrin may be a new target for the treatment of bronchial asthma.

Increased expression of pendrin in eosinophilic chronic rhinosinusitis with nasal polyps / Expressão aumentada de pendrina na rinossinusite crônica eosinofílica com pólipos

Abstract Introduction: Chronic rhinosinusitis with nasal polyps is a heterogeneous disease and appropriate diagnostic algorithms in individual cases are necessary for effective medical treatment. Objective: The purpose of this study was to clarify the relationship between the pendrin expression of nasal polyps and clinical and pathological characteristic features of eosinophilic chronic rhinosinusitis. Methods: A total of 68 patients were classified into eosinophilic chronic rhinosinusitis or non-eosinophilic chronic rhinosinusitis groups according to the degree of eosinophilic infiltration into the nasal polyps. Clinical, hematological, and immunohistochemical analyses were performed and statistically compared between both groups. Results: Thirty-eight were classified into eosinophilic chronic rhinosinusitis and 30 into non-eosinophilic chronic rhinosinusitis groups. There were no significant differences in age distribution, sex ratio, prevalence of asthma, or any other complications between the groups. The mean Lund-Mackay score and the number of serum eosinophils was significantly higher in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis groups. The pendrin expression was more frequently detected in the epithelial surface layer of nasal polyps in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis groups. In addition, mucin 5AC was more widely expressed in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis. Conclusion: Increased expression of pendrin and mucin 5AC in the nasal polyps would be associated with development of eosinophilic chronic rhinosinusitis. This finding could allow the development of a novel therapeutic agent targeted specifically to patients with eosinophilic chronic rhinosinusitis.

Resumo Introdução: A rinossinusite crônica com pólipos nasais é uma doença heterogênea e algoritmos diagnósticos apropriados em casos individuais são necessários para um tratamento médico eficaz. Objetivo: O objetivo deste estudo foi esclarecer a relação entre a expressão da pendrina de pólipos nasais e propriedades clínicas e patológicas características da rinossinusite crônica eosinofílica. Método: Um total de 68 pacientes foram classificados como tendo rinossinusite crônica eosinofílica ou rinossinusite crônica não eosinofílica de acordo com o grau de infiltração eosinofílica nos pólipos nasais. Análises clínicas, hematológicas e imunohistoquímicas foram realizadas e comparadas estatisticamente entre os dois grupos. Resultados: Entre os pacientes, 38 apresentavam rinossinusite crônica eosinofílica e constituíram o grupo 1; 30 tinham rinossinusite crônica não eosinofílica e constituíram o grupo 2. Não houve diferenças significantes na distribuição etária, razão entre os sexos, prevalência de asma ou qualquer outra complicação entre os grupos. O escore médio de Lund-Mackay e o número de eosinófilos séricos foram significantemente maiores no grupo com rinossinusite crônica eosinofílica do que no grupo com rinossinusite crônica não eosinofílica. A expressão da pendrina foi mais frequentemente detectada na camada epitelial superficial dos pólipos nasais na rinossinusite crônica eosinofílica do que no grupo com rinossinusite crônica não eosinofílica. Além disso, mucina 5AC foi mais amplamente expressa na rinossinusite crônica eosinofílica do que na rinossinusite crônica não eosinofílica. Conclusão: O aumento da expressão da pendrina e mucina 5AC nos pólipos nasais estaria associado ao desenvolvimento de rinossinusite crônica eosinofílica. Esse achado pode permitir o desenvolvimento de um novo agente terapêutico voltado especificamente para pacientes com rinossinusite crônica eosinofílica.

Expression of Pendrin gene (SLC26A4) and protein in multinodular goiter / 中华内分泌外科杂志

Objective To explore the expression of the Pendrin gene (SLC26A4) and protein in multinodular goiter.Methods Thyroid tissues were obtained from 40 multinodular goiter patients undergoing surgery while the control group were obtained from 40 nomal thyroid tissues.RT-PCR was used to test SLC26A4 gene while western blot and immunohistochemistry were used to test Pendrin protein expression and distribution.Results SLC26A4 mRNA expression in multinodular goiter tissue was significantly increased in comparison with normal nodular tissues (t=2.663,P=0.011).Pendrin protein expression in multinodular goiter group was higher than that in normal tissue (t=2.286,P=0.026).The immunohistochemistry results showed that the Pendrin protein in multinodular goiter was mainly located in cytoplasm.There was positive expression in 24 patients (60％) in multinodular goiter group,while it was in 14 patients (35％) in the normal control group.The difference was significant (X2=5.013,P=0.025).Pendrin protein mainly expressed in cytoplasm in multinodular goiter tissue while it was mainly in cytomembrane in the normal control group.Conclusion SLC26A4 mRNA and its coding protein Pendrin expression are increased in multinodular goiter group,and mainly located in cytoplasm,indicating that iodide transporter function may be damaged when multinodular goiter occurs.

Renal intercalated cells and blood pressure regulation

Type B and non-A, non-B intercalated cells are found within the connecting tubule and the cortical collecting duct. Of these cell types, type B intercalated cells are known to mediate Cl⁻ absorption and HCO₃⁻ secretion largely through pendrin-dependent Cl⁻/HCO₃⁻ exchange. This exchange is stimulated by angiotensin II administration and is also stimulated in models of metabolic alkalosis, for instance after aldosterone or NaHCO₃ administration. In some rodent models, pendrin-mediated HCO₃⁻ secretion modulates acid-base balance. However, the role of pendrin in blood pressure regulation is likely of more physiological or clinical significance. Pendrin regulates blood pressure not only by mediating aldosterone-sensitive Cl⁻ absorption, but also by modulating the aldosterone response for epithelial Na⁺ channel (ENaC)-mediated Na⁺ absorption. Pendrin regulates ENaC through changes in open channel of probability, channel surface density, and channels subunit total protein abundance. Thus, aldosterone stimulates ENaC activity through both direct and indirect effects, the latter occurring through its stimulation of pendrin expression and function. Therefore, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contributory role of pendrin in distal nephron function and blood pressure.

Renal intercalated cells and blood pressure regulation

Type B and non-A, non-B intercalated cells are found within the connecting tubule and the cortical collecting duct. Of these cell types, type B intercalated cells are known to mediate Cl⁻ absorption and HCO₃⁻ secretion largely through pendrin-dependent Cl⁻/HCO₃⁻ exchange. This exchange is stimulated by angiotensin II administration and is also stimulated in models of metabolic alkalosis, for instance after aldosterone or NaHCO₃ administration. In some rodent models, pendrin-mediated HCO₃⁻ secretion modulates acid-base balance. However, the role of pendrin in blood pressure regulation is likely of more physiological or clinical significance. Pendrin regulates blood pressure not only by mediating aldosterone-sensitive Cl⁻ absorption, but also by modulating the aldosterone response for epithelial Na⁺ channel (ENaC)-mediated Na⁺ absorption. Pendrin regulates ENaC through changes in open channel of probability, channel surface density, and channels subunit total protein abundance. Thus, aldosterone stimulates ENaC activity through both direct and indirect effects, the latter occurring through its stimulation of pendrin expression and function. Therefore, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contributory role of pendrin in distal nephron function and blood pressure.

Locus DFNB4 -acueducto vestibular dilatado- comportamiento audio-vestibular / Locus DFNB4 -enlarged vestibular aqueduct- behavior audio vestibular / Locus DFNB4 - aqueduto vestibular dilatada - comportamentoaudio-vestibular

Introducción: el acueducto vestibular dilatado, denominado en la literatura internacional EVA, porEnlarged Vestibular Aqueduct, ha sido reportadopor afectar hasta el 15% de la población pediátrica con hipoacusia neurosensorial. En su génesis compartecon Pendred en el Locus DFNB4, el Gen SLC26A4en el cromosma 7q22-31.1. No se conoce bienel comportamiento y la evolución de esta entidad,debido a la gran variabilidad genotípica y fenotípicaque presenta...

Introduction: Dilated Vestibular Aqueduct, known in the international literature Enlarged Vestibular Aqueduct (EVA) has been reported to affect up to 15% of the pediatric population with hearing loss Sensory Neuro. In its genesis shares with pendred in the locus DFNB4 the SLC26A4 gene in the cromosma 7q22-31.1. It is not well understood and evolution behavior of this entity, due to the great variability genotypic and phenotypic presented...

Introdução: Aqueduto vestibular dilatada conhecido na literatura internacional Enlarged Vestibular Aqueduct (EVA) tem sido relatada a afetar até 15% da população pediátrica com perda auditiva sensorial neuro. Em suas ações genesis com Pendred no Locus DFNB4 o gene SLC26A4 na 7q22-31.1 cromosma. Elenão é bem compreendida e o comportamento de evolução dessa entidade, devido à grande variabilidade genotípica e fenotípica apresentada...

SLC26A4 Mutations in Korean Population / 대한이비인후과학회지

SLC26A4 mutations are common cause of congenital hearing loss in East Asia. The carrier frequency of SLC26A4 mutations is 1 in 75 in Korean populations. The SLC26A4 mutation spectrum varies according to the population. The most common mutation in Korean is replacement of histidine by arginine at codon 723 followed by exchange of guanine for adenine at the consensus acceptor splice site of intron 7, adenine to guanine change at position +3 transition donor splice site of intron 9, methionine to valine at position 147, and frameshift mutation by insertion T at N-terminal 2. Recent studies analyzed the genotype-phenotype correlation of SLC26A4 mutation and suggested that surface expression ratio of pendrin and residual anion exchange activity was related to the genotype of SLC26A4 mutations. The targeted drug to Korean SLC26A4 mutations would be helpful in preserving hearing in patients with SLC26A4 mutations.

Effects of insulin-like growth factor-Ⅰ and transforming growth factor-β1 on the expressions of sodium iodide symporter and pendrin mRNA in a placental villous trophoblast cell line exposed to different levels of iodine / 中华地方病学杂志

Objective To observe the effects of insulin-like growth factor-Ⅰ (IGF-Ⅰ) and transforming growth factor-β1 (TGF-β1) on the expressions of sodium iodide symporter(NIS) and pendrin mRNA in a placental villous trophoblast cell line(HPT-8) exposed to different levels of iodine.Methods HPT-8 cells were cultured in vitro in the culture flask and divided into low iodine group-Ⅰ (LI-Ⅰ),low iodine group-Ⅱ (LI-Ⅱ),control group,high iodine group-Ⅰ (HI-Ⅰ) and high iodine group-Ⅱ (HI-Ⅱ) that exposed to different concentrations of iodine (0,5,50,500,5000 μg/L).After cell cultured for 24 h,the followings were added to the culture medium:iodine plus IGF-Ⅰ(0.050 mg/L),iodine plus TGF-β1 (0.001 mg/L).After cultured for another 24 h,total RNA was extracted,the expressions of NIS and pendrin mRNA of HPT-8 cells were determined by real-time quantitative PCR.Results The expression of NIS mRNA in HPT-8 cells:at different levels of iodine,the differences of NIS mRNA expression between groups were statistically significant in group with iodine alone(F =3.612,P ＜ 0.01).The expression of NIS mRNA in LI-Ⅰ group(0.44 ± 0.21) was significantly lower than that of control group(1.25 ± 0.77,P＜ 0.01).At the same level of iodine,in LI-Ⅰ group and HI-Ⅰ group,the differences of NIS mRNA expression within groups were statistically significant (F =13.632,6.900,all P ＜ 0.01).In LI-Ⅰ group,the expressions of NIS mRNA were higher in iodine plus IGF-Ⅰ(1.13 ± 0.38) and iodine plus TGF-β1 (0.81 ± 0.34) than that of pure iodine(0.44 ± 0.21,P ＜ 0.01 or ＜ 0.05);in HI-Ⅰ group,the expression of NIS mRNA was lower in iodine plus TGF-β1 (0.62 ± 0.30) than that of pure iodine(1.23 ± 0.91,P ＜ 0.01).The expression of pendrin mRNA in HPT-8 cells:at different levels of iodine,the differences of pendrin mRNA expression between groups were statistically significant in group with iodine alone(F =12.717,P ＜ 0.01).The expression of pendrin mRNA in LI-Ⅰ group(0.59 ± 0.15) was significantly lower than that of control group(1.03 ± 0.14,P ＜ 0.01) ; HI-Ⅰ group(1.29 ± 0.31) was higher than control group(P ＜ 0.05).At the same level of iodine,the differences of pendrin mRNA expression within groups were statistically significant in LI-Ⅰ,LI-Ⅱ,control and HI-Ⅰ groups (F=12.588,4.588,8.679,8.445,all P ＜ 0.01).In LI-Ⅰ,LI-Ⅱ and control groups,the expressions of pendrin mRNA were significantly higher in iodine plus IGF-Ⅰ(1.68 ± 0.82,1.51 ± 0.79,1.50 ± 0.51) than that of pure iodine(0.59 ± 0.15,0.89 ± 0.22,1.03 ± 0.14,all P ＜ 0.01); in HI-Ⅰ group,the expression of pendrin mRNA was significantly lower in iodine plus TGF-β1 (0.78 ± 0.20) than that of pure iodine(1.29 ± 0.31,P ＜ 0.01).Conclusions In the case of iodine deficiency,the mRNA expressions of NIS and pendrin in HPT-8 cells are decreased and the iodine uptake ability is decreased; the expression of pendrin mRNA in HPT-8 cells is increased and placental iodine uptake is increased under the conditions of mild iodine excessive.IGF-Ⅰ and TGF-β1 play a role in the placental iodine uptake through increasing iodine uptake under the conditions of iodine deficiency and decreasing iodine uptake under the conditions of iodine excessive.

Role of Pendrin in Acid: base Balance

Pendrin (SLC26A4) is a Na+-independent Cl-/HCO3- exchanger which is expressed in the apical membranes of type B and non-A, non-B intercalated cells within the distal convoluted tubule, the connecting tubule, and the cortical collecting duct. In those segments it mediates HCO3- secretion and chloride (Cl-) absorption. In mice, no renal abnormalities are observed under basal conditions, and individuals with genetic disruption of the pendrin (SLC26A4) gene (Pendred syndrome) have normal acid-base balance. In contrast, there are definite differences under conditions wherein the transporter is stimulated. In animal studies, pendrin (SLC26A4) is upregulated with aldosterone analogues, Cl- restriction, and metabolic alkalosis, and is down-regulated with Cl loading and metabolic acidosis, independently. However, the exact role of pendrin in humans has not been established to date, and further examinations are necessary.

Pendred syndrome in a large consanguineous Brazilian family caused by a homozygous mutation in the SLC26A4 gene / Síndrome de Pendred causada por mutação em homozigoze no gene SLC26A4 em uma família brasileira consangüínea

Pendred Syndrome (PS) is an autossomal recessive disorder characterized by sensorineural deafness, goiter and iodide organification defect. The hearing loss is associated with inner ear abnormalities, ranging from an isolated enlarged vestibular aqueduct (EVA) to a typical coclear dysplasia. Mutations in the gene that encodes pendrin (SLC26A4), a chloride/iodide transporter, have been shown to be associated with PS. We describe the clinical and molecular characteristics of a large consanguineous family harboring a mutation in the SLC26A4 gene. The proband was a 26-year-old deaf Brazilian woman who presented a bulky multinodular goiter and hypothyroidism since puberty. Five other siblings were deaf: one brother had a similar phenotype, three siblings also had goiters but normal thyroid function tests, and one brother had only a subtle thyroid enlargement. Other 4 siblings had no thyroid or hearing disorder. Parents were first degree cousins and had normal hearing. The mother was healthy, except for subclinical hypothyroidism; the father was deceased. A perchlorate test in the proband showed a discharge of 21 percent of the incorporated iodide 2h after the administration of 1g of KClO4. Audiological examinations showed profound hearing loss in all deaf subjects; CT and MRI of the temporal bones showed EVA in all of them. Genomic DNA was isolated from whole blood, from the 6 affected and 4 unaffected siblings, the mother and control. The coding region of the PDS gene (exons 2-21), including exon/intron boundaries, were amplified by PCR and sequenced. A single base-pair (T) deletion at position 1197 of exon 10 was detected in homozygous state in the 6 deaf siblings. The mother and 2 unaffected siblings were heterozygous for this mutation, which has been described by Everett et al. The 1197delT mutation is predicted to result in a frameshift and a truncated protein. The existence of PS phenocopies and intrafamilial phenotypic variability are...

A syndrome de Pendred (SP) é uma doença autossômica recessiva caracterizada por surdez neurossensorial, bócio e defeito de organificação do iodo. A perda auditiva está associada a anormalidades do ouvido interno, desde a dilatação isolada do aqueduto vestibular (DAV) até uma típica displasia coclear. Mutações no gene que codifica a pendrina (SLC26A4), um transportador de cloreto/iodeto, têm sido associadas à SP. Descrevemos as características clínicas e moleculares de uma grande família consangüínea portadora de uma mutação no gene SLC26A4. O caso-índice era uma paciente do sexo feminino, brasileira, 26 anos, portadora de surdez congênita, que apresentava um volumoso bócio multinodular e hipotireoidismo desde a puberdade. Outros cinco irmãos eram surdos: um irmão tinha fenotipo semelhante, três também tinham bócio, porém com função tiroideana normal e um irmão tinha apenas um discreto aumento da tiróide. Outros quatro irmãos não apresentavam alteração tiroideana ou auditiva. Os pais eram primos de primeiro grau e tinham audição normal. A mãe era saudável, exceto por hipotireoidismo subclínico; o pai era falecido. O teste do perclorato no caso-índice revelou a liberação de 21 por cento do iodo incorporado duas horas após a administração de 1 g de KClO4. Os exames audiológicos mostraram perda auditiva profunda em todos os indivíduos afetados; TC e RMN dos ossos temporais mostraram DAV em todos eles. O DNA genômico foi isolado do sangue total dos seis irmãos afetados e dos quatro não-afetados, da mãe e do controle. A região codificante do gene PDS (éxons 2-21), incluindo as junções éxon/íntron, foram amplificadas por PCR e seqüenciadas. Foi detectada a deleção de uma base (T) na posição 1197 do éxon 10, em homozigoze, nos seis irmãos afetados. A mãe e dois irmãos não-afetados eram heterozigotos para a mutação, que foi descrita inicialmente por Everett e cols. A mutação 1197delT provavelmente resulta em um erro de fase de leitura (frameshift)...

Expression of an Anion Exchanger Pendrin in Human Kidney / 대한해부학회지

It has been reported that new apical anion exchanger perndrin, encoded by the pendred syndrome (PDS/pds, Slc26A4) gene, was expressed in the AE1-negative intercalated cells of rat and mouse kidneys. The purpose of this study was performed that expression of pendrin in the subtypes of intercalated cells in human kidney. The normal human renal tissues obtained from nephrotomized kidneys for renal cell carcinoma were fixed in periodate-lysine-paraformalde-hyde, and processed for immunohistochemistry. Subtypes of intercalated cells were identified by using antibodies for H(+)-ATPase and AE1, and connecting tubule cells and principal cells of collecting duct were identified using antibodies for calbindin D28K and AQP2, respectively. In human kidney, pendrin was expressed in the apical domain of AE1-negative intercalated cells including type B cells with diffuse and/or basolateal H(+)-ATPase, non A-non B (non -A/B) type intercalated cells with apical H(+)-ATPase and bipolar type of intercalated cells with apical and basolateral H(+)-ATPase. The AQP2-positive principal cells of cortical collecting duct were also had apical pendrin immunoreactivity. However, there was no pendrin immunoreactivity in AE1-positive type A intercalated cells, calbindin D28K-positive connecting tubule cells, and AQP2-positive medullary collecting duct. These results suggest that pendrin is an apical anion exchanger not only in the AE1-negative intercalated cells (type B, non-A/B and bipolar cells) but also in the principal cells of cortical collecting duct, and has an essential role in HCO3-secretion in human kidney.

The Expression of NIS and Pendrin in Thyroid Cancer Tissues with Real Time RT-PCR / 대한내분비외과학회지

PURPOSE: It has not been clearly investigated how iodine can be trapped from the extracellular space into thyroid follicular cells, the defective iodide-trapping mechanism appears to be an early and constant feature during oncogenic transformation of thyroid cells. In recent studies, NIS and pendrin are associated with the trapping process. Thus, in order to reveal this uncertain relationship, each of the quantitative expressions of NIS and pendrin in various thyroid tissues were evaluated by real time RT-PCR. METHODS: This study included 63 patients who had undergone thyroidectomy in Uijongbu St. Mary's hospital from Jan. 2000 to Jan. 2003. 13 cases of normal thyroid, 17 cases of hypofunctioning thyroid adenomas, and 33 cases of thyroid cancer were examined. The thyroid cancer group was further divided into high and low risk group according to the AMES score, and the NIS and pendrin levels were compared between the two groups. Real time RT-PCR was conducted with the extracted RNAs, using GAPDH as the control. RESULTS: As for pendrin, its expression was decreased by 7% in the thyroid adenoma group compared with that of normal thyroid, while there was a 59% decrease in thyroid cancer cases. NIS expression was decreased by 20% in the thyroid adenoma group, and a 40% decrease was found in thyroid cancer group. Due to the impediment of pendrin in both high and low risk group of thyroid cancer, there was a 19% decrease in the high risk group compared with the low risk group. As for the impediment of NIS in the high risk group, an increase of 30% was found. However, no statistical significance was shown (P=0.344 vs P=0.688). CONCLUSION: According to this study, it can be inferred that the decrease in the expressions of NIS and pendrin are related to tumorigenesis of thyroid cancer. Also, further research is needed to reveal the cause of genetic transformation, as well as the value of utilization of NIS and pendrin as tumor markers.

Relation Between Iodide Transporters and Thyroid Diseases / 中国普外基础与临床杂志

Objective To investigate the clinical significance of the three iodide transporters in thyroid diseases. Methods Literatures about the Na+/I-symporter (NIS), pendrin and human apical iodide transporter (hAIT) in recent years were reviewed and their expressions in different thyroid diseases were also analyzed. Results NIS proteins express at the basolateral membrane of thyrocytes in normal thyroid tissue, while pendrin and hAIT proteins are limited to the apical membrane of thyrocytes lining in the follicular lumen. In the tissues of thyroid carcinomas, it was found that the NIS proteins expressed in the cytoplasm and their expressions decreased; The mutation of NIS gene may be one of the main causes of congenital hypothyroidism. The expression of prendrin protein may be related to the function of follicles: its expression level increased significantly both in Graves diseases and toxic adenomas, but significantly decreased in differentiated thyroid carcinoma. However, the correlation between the decrease and the degrees of differentiation of carcinoma cell line are still disputable. The expression of hAIT protein does not significantly altered in hyperfunctioning tissues. It only slightly decreased occasionally in hypofunctioning adenomas, but it decreased significantly in thyroid carcinomas. Conclusion The abnormal expressions of the three iodide transporters may be related closely with the type of thyroid diseases. However, their pathogenic mechanisms and the causes of their abnormal expression are still unknown, which need to be studied further.