ABSTRACT
The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IP3R3) in renal cyst development in autosomal dominant polycystic kidney disease (ADPKD). 2-aminoethoxy-diphenyl borate (2-APB) and shRNA were used to suppress the expression of IP3R3. The effect of IP3R3 on cyst growth was investigated in Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney specific Pkd1 knockout (PKD) mouse model. The underlying mechanism of IP3R3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IP3R3 was significantly increased in the kidneys of PKD mice. Inhibiting IP3R3 by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model. Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IP3R3, which was accompanied by a subcellular redistribution process in which IP3R3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IP3R3 further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle. These results suggest that the expression and subcellular distribution of IP3R3 are involved in promoting renal cyst development, which implies IP3R3 as a potential therapeutic target of ADPKD.
Subject(s)
Animals , Dogs , Mice , Cysts/genetics , Inositol 1,4,5-Trisphosphate Receptors/pharmacology , Kidney/metabolism , Polycystic Kidney Diseases/metabolism , Polycystic Kidney, Autosomal Dominant/drug therapy , Madin Darby Canine Kidney CellsABSTRACT
Abstract Giardia duodenalis is divided into eight assemblages (named A to H). Isolates of assemblage A are divided into four sub-assemblages (AI, AII, AIII and AIV). While isolates of sub-assemblage AII are almost exclusively detected in human hosts, isolates of assemblage B are encountered in a multitude of animal hosts and humans. Here, we isolated single cysts of G. duodenalis from a human stool sample and found that one of them had overlaps of assemblage AII and B alleles and an unexpectedly high number of variants of the beta-giardin (Bg) and GLORF-C4 (OrfC4) alleles. In addition, one of the Bg alleles of that cyst had a fragment of sub-assemblage AII interspersed with fragments of assemblage B, thus indicating that this allele may be a recombinant between sequences A and B. Our results are unprecedented and put a check on the statement that different assemblages of G. duodenalis represent species with different host specificities.
Resumo A espécie Giardia duodenalis é dividida em oito grupos (nomeados de A a H). Isolados do grupo A são divididos em quatro subgrupos (AI, AII, AIII and AIV). Enquanto isolados do subgrupo AII são detectados quase exclusivamente em hospedeiros humanos, isolados do subgrupo B são encontrados em uma grande variedade de hospedeiros entre animais e humanos. Neste trabalho, foi constatado que, dentre diversos cistos individualizados de G. duodenalis provenientes de fezes de origem humana, um cisto continha os alelos AII e B e um número inesperado de variantes de alelos codificadores de beta giardina e GLORF-C4. Ainda, um dos alelos beta giardina desse cisto possuía fragmentos AII intercalando um fragmento B, indicando que esse alelo pode ser um recombinante entre alelos AII e B. Os resultados aqui apresentados são inéditos e colocam em dúvida o conceito atual de que os diferentes grupos de G. duodenalis representam espécies distintas com diferentes graus de especificidade por hospedeiros.
Subject(s)
Animals , Protozoan Proteins/genetics , Giardia lamblia/genetics , Cysts/genetics , Cytoskeletal Proteins/genetics , Alleles , Genetic Carrier Screening/veterinary , Giardia lamblia/classification , GenotypeABSTRACT
Cystic medial necrosis (CMN) is a disorder of large arteries, in particular the aorta, characterized by an accumulation of basophilic ground substance in the media with cyst-like lesions. CMN is known to occur in certain connective tissue diseases such as Marfan syndrome, Ehlers-Danlos syndrome, and annuloaortic ectasia, which usually result from degenerative changes in the aortic wall. The relationships between CMN and congenital heart defects as well as other disorders have been evidenced. The mechanisms are still controversial, even though many molecular studies have been conducted. The aim of the present article is to provide a comprehensive overview of the CMN lesion in terms of pathologic features, clinical implications and etiologies based on molecular research results.
A necrose cística da média (NCM) é uma desordem das grandes artérias, em particular a aorta, caracterizada por acúmulo de substância basofílica na camada média com lesões císticas-símile. É sabido que a NCM ocorre em certas doenças do tecido conjuntivo tal como síndrome de Marfan, síndrome de Ehlers-Danlos, e ectasia ânulo-aórtica, que normalmente resulta de mudanças degenerativas na parede aórtica. A relação entre NCM e defeitos congênitos do coração, assim como outras desordens, tem sido evidenciada. Os mecanismos são ainda controversos, embora muitos estudos moleculares tenham sido conduzidos. O objetivo do presente artigo é fornecer uma visão geral da NCM em termos de características patológicas, implicações clínicas e etiologia baseada em resultados de pesquisa molecular.
Subject(s)
Humans , Aortic Aneurysm, Thoracic , Cysts , Aortic Aneurysm, Thoracic/complications , Aortic Aneurysm, Thoracic/genetics , Aortic Aneurysm, Thoracic/pathology , Cysts/complications , Cysts/genetics , Cysts/pathologyABSTRACT
A 45-year-old woman presented with a mass in the right hypochondrium and shortness of breath. The mass was felt up to 4.5 inches below the right costal margin and its dullness on percussion was continuous with liver dullness. Ultrasonography (USG) of abdomen revealed enlargement of the left lobe of the liver with multiple cysts of varying sizes. Left liver lobectomy was done, histology of which showed multiple cysts lined by cuboidal to columnar epithelium. A small amount amount of normal liver parenchyma between the cysts was observed. A diagnosis of Adult polycystic liver disease (APLD) was given.