A review on the effect of Claudin-18 on bronchopulmonary dysplasia in preterm infants / 中国当代儿科杂志

Bronchopulmonary dysplasia (BPD) has the main manifestations of pulmonary edema in the early stage and characteristic alveolar obstruction and microvascular dysplasia in the late stage, which may be caused by structural and functional destruction of the lung epithelial barrier. The Claudin family is the main component of tight junction and plays an important role in regulating the permeability of paracellular ions and solutes. Claudin-18 is the only known tight junction protein solely expressed in the lung. The lack of Claudin-18 can lead to barrier dysfunction and impaired alveolar development, and the knockout of Claudin-18 can cause characteristic histopathological changes of BPD. This article elaborates on the important role of Claudin-18 in the development and progression of BPD from the aspects of lung epithelial permeability, alveolar development, and progenitor cell homeostasis, so as to provide new ideas for the pathogenesis and clinical treatment of BPD.

La diabetes mellitus experimental produce aumento en la expresión de iNOS y altera la vía paracelular de la absorción intestinal de calcio / Experimental diabetes mellitus produces increased iNOS expression and alters the paracellular pathway of intestinal calcium absorption

Previamente hemos demostrado que la diabetes mellitus tipo 1 experimental (D.m.1) inducida por estreptozotocina (STZ) produce estrés oxidativo intestinal en las primeras etapas de la enfermedad, lo que conduce a la inhibición de la absorción intestinal de Ca+2, alterando la vía transcelular del transporte del catión. El objetivo de este trabajo fue estudiar la vía paracelular del transporte del Ca+2 y analizar si la D.m.1 induce estrés nitrosativo a nivel duodenal. Se utilizaron ratas Wistar machos a las que se inyectaron 60 mg STZ/kg de peso corporal; se sacrificaron a los 30 días postratamiento. Se determinó la expresión génica y proteica de claudina 2 y 12, proteínas involucradas en el transporte paracelular del Ca+2. En la mucosa duodenal se determinó el contenido de óxido nítrico (NO) y la expresión proteica de óxido nítrico sintasa inducible (iNOS). Los resultados revelaron que la expresión génica de claudina 2 en las ratas diabéticas fue más del doble en comparación con la de los controles, mientras que la expresión génica de claudina 12 fue similar en ambos grupos. La expresión proteica de claudina 2 y 12 aumentó en las ratas diabéticas. El contenido de NO fue similar en ambos grupos; sin embargo, la expresión proteica de iNOS fue mayor en las ratas diabéticas en comparación con la de las ratas controles. En conclusión, la D.m.1 experimental se acompaña de estrés oxidativo y de aumento en la expresión proteica de iNOS, alterándose la vía paracelular de absorción de Ca+2 como un mecanismo compensatorio. (AU)

We have previously shown that experimental type 1 diabetes mellitus (D.m.1) produced by streptozotocin (STZ) in rats causes intestinal oxidative stress in the early stages of the disease, which leads to the inhibition of intestinal Ca2+ absorption, altering the transcellular Ca2+ pathway. The aim of this work was to study the paracellular Ca2+ pathway and analyze if D.m.1 induces duodenal nitrosative stress. The animals were assigned to two groups: 1) control rats, and 2) STZ-induced diabetic rats (60 mg/kg b.w.). Rats were sacrificed 30 days after induction of diabetes. The gene and protein expression of claudin 2 and 12, proteins involved in paracellular Ca2+ pathway, was determined as well as the nitric oxide (NO) content and protein expression of iNOS in rat duodenum mucosa. The results revealed that claudin 2 expression was more that double in diabetic rats compared to control rats at 30 days, while the gene expression of claudin 12 was similar in both groups. The protein expression of claudin 2 and 12 increased in the diabetic rats. NO content was similar in both groups, but the iNOS protein expression was enhanced in diabetic rats. To conclude, the experimental type I D.m.1 is accompanied by duodenal oxidative stress, increase iNOS protein expression and alteration of the paracellular Ca2+ pathway as a compensatory mechanism. (AU)

Five years results after intrafamilial kidney post-transplant in a case of familial hypomagnesemia due to a claudin-19 mutation / Resultado cinco anos pós-transplante renal intrafamiliar em um caso de hipomagnesemia familiar devido a mutação da claudina-19

Introduction: Familial Hypomagnesaemia with hypercalciuria and nephrocalcinosis, with severe ocular impairment secondary to claudin-19 mutation, is a rare recessive autossomic disorder. Its spectrum includes renal Mg2+ wasting, medullary nephrocalcinosis and progressive chronic renal failure in young people. Objective: To report a case of kidney transplantation father to daughter in a familial occurrence of severe bilateral nephrocalcinosis associated with ocular impairment in a non-consanguineous Brazilian family, in which two daughters had nephrocalcinosis and severe retinopathy. Methods: The index case, a 19 years-old female, had long-lasting past medical history of recurrent urinary tract infections, and the abdominal X-ray revealed bilateral multiple renal calcifications as well as ureteral lithiasis, and she was under haemodialysis. She had the diagnosis of retinitis pigmentosa in the early neonatal period. The other daughter (13 years-old) had also nephrocalcinosis with preserved kidney function, retinopathy with severe visual impairment, and in addition, she exhibited hypomagnesaemia = 0.5 mg/dL and hypercalciuria. The other family members (mother, father and son) had no clinical disease manifestation. Mutation analysis at claudin-19 revealed two heterozygous missense mutations (P28L and G20D) in both affected daughters. The other family members exhibited mutant monoallelic status. In despite of that, the index case underwent intrafamilial living donor kidney transplantation (father). Conclusion: In conclusion, the disease was characterized by an autosomal recessive compound heterozygous status and, after five years of donation the renal graft function remained stable without recurrence of metabolic disturbances or nephrocalcinosis. Besides, donor single kidney Mg2+ and Ca2+ homeostasis associated to monoallelic status did not affect the safety and the usual living donor post-transplant clinical course. .

Introdução: Hipomagnesemia familiar com hipercalciúria e nefrocalcinose, com grave envolvimento ocular, por mutação no gene da claudina-19, é uma doença rara autossômica recessiva. Seu espectro inclui perda renal de magnésio, nefrocalcinose medular e doença renal progressiva em crianças e adolescentes. Objetivo: Relatar um caso de transplante renal pai para filha em uma ocorrência familiar de nefrocalcinose bilateral grave associada com comprometimento ocular em uma família brasileira não consangüínea, na qual duas filhas apresentavam nefrocalcinose e retinopatia severa. Métodos: O caso índice, uma mulher de 19 anos de idade, tinha longa história pregressa de infecção urinária de repetição, o raio-X abdominal revelava calcificações renais múltiplas bilaterais, bem como litíase ureteral, e estava sob hemodiálise. Havia um diagnóstico prévio de retinite pigmentosa no período neonatal precoce. A outra filha (13 anos de idade) também apresentava nefrocalcinose com função renal preservada, retinopatia com grave deficiência visual, e além disso, ela exibia hipomagnesemia = 0,5 mg/dL e hipercalciúria. Os outros membros da família (mãe, pai e filho) não tinham nenhuma manifestação clínica da doença. A análise mutacional no gene da claudin-19 revelou duas mutações heterozigotas (P28L e G20D) em ambas as filhas afetadas. Os outros membros da família apresentavam estado mutante monoalélico. Apesar disso, o caso índice foi submetido a transplante de rim com doador vivo intrafamiliar (pai). Conclusão: Em conclusão, a doença foi caracterizada por um estado heterozigoto recessivo composto autossômico e após cinco anos de doação a função do enxerto ...

Genetic and molecular analysis of the CLDN14 gene in Moroccan family with non-syndromic hearing loss.

BACKGROUND: Hearing loss is the most prevalent human genetic sensorineural defect. Mutations in the CLDN14 gene, encoding the tight junction claudin 14 protein expressed in the inner ear, have been shown to cause non‑syndromic recessive hearing loss DFNB29. AIM: We describe a Moroccan SF7 family with non‑syndromic hearing loss. We performed linkage analysis in this family and sequencing to identify the mutation causing deafness. MATERIALS AND METHODS: Genetic linkage analysis, suggested the involvement of CLDN14 and KCNE1 gene in deafness in this family. Mutation screening was performed using direct sequencing of the CLDN14 and KCNE1 coding exon gene. RESULTS: Our results show the presence of c.11C>T mutation in the CLDN14 gene. Transmission analysis of this mutation in the family showed that the three affected individuals are homozygous, whereas parents and three healthy individuals are heterozygous. This mutation induces a substitution of threonine to methionine at position 4. CONCLUSION: These data show that CLDN14 gene can be i mplicated in the development of hearing loss in SF7 family; however, the pathogenicity of c.11C>T mutation remains to be determined.

Apical acidity decreases inhibitory effect of omeprazole on Mg2+ absorption and claudin-7 and -12 expression in Caco-2 monolayers

Clinical studies reported hypomagnesaemia in long-term omeprazole usage that was probably due to intestinal Mg2+ wasting. Our previous report demonstrated the inhibitory effect of omeprazole on passive Mg2+ transport across Caco-2 monolayers. The present study aimed to identify the underlying mechanism of omeprazole suppression of passive Mg2+ absorption. By using Caco-2 monolayers, we demonstrated a potent inhibitory effect of omeprazole on passive Mg2+, but not Ca2+, transport across Caco-2 monolayers. Omeprazole shifted the %maximum passive Mg2+ transport-Mg2+ concentration curves to the right, and increased the half maximal effective concentration of those dose-response curves, indicating a lower Mg2+ affinity of the paracellular channel. By continually monitoring the apical pH, we showed that omeprazole suppressed apical acid accumulation. Neomycin and spermine had no effect on passive Mg2+ transport of either control or omeprazole treated monolayers, indicating that omeprazole suppressed passive Mg2+ transport in a calcium sensing receptor (CaSR)-independent manner. The results of western blot analysis showed that omeprazole significantly suppressed claudin (Cldn)-7 and -12, but not Cldn-2, expression in Caco-2 cells. By using apical solution of pH 5.5, 6.0, 6.5, and 7.0, we found that apical acidity markedly increased passive Mg2+ transport, Mg2+ affinity of the paracellular channel, and Cldn-7 and -12 expression in Caco-2 monolayers. Apical acidity abolished the inhibitory effect of omeprazole on passive Mg2+ transport and Cldn-7 and -12 expression. Our results provided the evidence for the regulation of intestinal passive Mg2+ absorption by luminal acidity-induced increase in Cldn-7 and -12 expression.