Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis

Ohta, Eriko; Itoh, Tomohiro; Nemoto, Tomomi; Kumagai, Jun; Ko, Shigeru B. H.; Ishibashi, Keiichiro; Ohno, Mayuko; Uchida, Keiko; Ohta, Akihito; Sohara, Eisei; Uchida, Shinichi; Sasaki, Sei; Rai, Tatemitsu

doi:10.1152/ajpcell.00117.2009

Cited by 55 publications

(39 citation statements)

References 30 publications

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“…Decreased expression for at least 66% of these genes is due to direct PTF1A control (asterisks). For example, AQP12 is the intracellular water pump that concentrates secretory proteins during passage to and within zymogen granules (44). Its mRNA decreased to 24% by 6 days, and PTF1A and RBPJL bind a control region occupied by RNAPII and methylated H3K4 near its transcriptional start site (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The data sets for three control mice and three Ptf1a-cKO mice 14 days after the beginning of tamoxifen treatment have been reported previously (GEO accession number GSE70542) (23). The RNA-Seq data sets for five 6-day TAM-treated control mice (40,42,34,33, and 31 million aligned reads) and three 6-day TAM-treated Ptf1a-cKO mice (41,44, and 49 million aligned reads) for this study were acquired in the same manner (GEO accession number GSE86261).…”

Section: Mice the Generation Of The Mouse Lines With The Genotypes Pmentioning

confidence: 99%

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Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma. Loss of cellular identity has long been associated with tissue injury and a first step in cancer progression (for examples, see references 1 and 2). Maintenance of a specific cellular phenotype depends on the continued transcription of cell-type-specific genes, largely through open chromatin architecture (3, 4) maintained by a small group of lineage-restricted DNA-binding transcription factors (TFs) (5, 6) that establish a unique transcriptional regulatory network (7). Many physiologic or pathophysiologic perturbations can affect the differentiated state of a cell quantitatively, but fewer affect the state of differentiation qualitatively. Qualitative changes involve the acquisition of characteristics of another cell type (or types), often defined by one or a few cell-specific markers, in addition to the diminution of the original phenotype. Despite progress with cellular reprogramming (for example, see reference 8), the molecular and genetic mechanisms that maintain cellular identity within the context of adult organs remain incompletely understood. In this report, we show that inactivation of the transcriptional regulatory gene Ptf1a in adult pancreatic acinar cells has pleiotropic effects on gene expression that cause quantitative and multigene qualitative changes of acinar differentiation.The acinar cell of the pancreas has been an informative model of terminal cellular differentiation (9). Common cellular processes are greatly exaggerated in support of the prodigious synthesis, processing, storage, and exocytosis of secretory proteins. The pancreatic acinar cell has the most ribosomes (10) and the highest rate of protein synthesis (11) of any mammalian somatic cell; it synthesizes, stores, and secretes its weight in protein daily. Specialized cellular functions ...

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Section: Resultsmentioning

confidence: 99%

Section: Mice the Generation Of The Mouse Lines With The Genotypes Pmentioning

confidence: 99%

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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“…To obtain the ER from the mouse kidneys, an ER extraction kit (Imgenex, San Diego, CA) was used following the manufacturer's instructions as previously reported. 41 …”

Section: Isolation Of Er From the Kidneymentioning

confidence: 99%

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

Inoue

Sohara

Kobayashi

et al. 2014

Journal of the American Society of Nephrology

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We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(2/2) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg AQP11 )that express 33HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg AQP11 mice and rescued renal cystogenesis in AQP11(2/2) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(2/2) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(2/2) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/2) background increased the severity of cystogenesis in AQP11(2/2) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(2/2) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(2/2) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(2/2) mice could be a key mechanism of cystogenesis in AQP11(2/2) mice.

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“…An intriguing observation has been made by Ohta et al (86) who found AQP12 expressed in the rough endoplasmic reticulum (rER) of rat pancreatic acinar cells. In CCK-8 treated rats, AQP12 was present in the rER and also on the membranes of ZGs near the rER.…”

Section: Channels H 2 O Channelsmentioning

confidence: 97%

“…In CCK-8 treated rats, AQP12 was present in the rER and also on the membranes of ZGs near the rER. Furthermore, AQP12 knockout mice were more prone to caerulein-induced pancreatitis (86). The authors suggested that AQP12 may be involved in the mechanisms underlying the proper generation, maturation and trafficking of ZGs in the secretory pathway and that adequate H 2 O flux may be necessary for this process to function adequately.…”

Section: Channels H 2 O Channelsmentioning

confidence: 99%

Channels and Transporters in Zymogen Granule Membranes and their Role in Granule Function: Recent Progress and a Critical Assessment

Thévenod

The Pancreapedia: Exocrine Pancreas Knowledge Base

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Secretory granules are located at the apex of pancreatic acinar cells. Secretagogues bind to their receptors at the basolateral membrane of acinar cells and trigger the activation of intracellular signaling pathways to elicit fusion of secretory granules with the apical plasma membrane that is followed by exocytosis of digestive pro-enzymes (the "zymogens") into the lumen. This regulated discharge of stored macromolecules is accompanied by the secretion of solutes and water to the cell exterior to hydrate these protein-rich secretory products. Previous functional and pharmacological studies in pancreatic acinar cells and zymogen granules (ZG) had suggested that ion channels and transporters are expressed in the membrane of ZG where they contribute to maturation, fusion, exocytosis and/or fluidization of zymogens. This chapter reviews studies that have been largely published in the postgenomic era and combined biochemical, immunological, electrophysiological, pharmacological, and/or occasionally knockout methodologies to identify cloned transporters and ion channels in the membrane of ZG. Available experimental evidence indicates the presence of several ion channel and transporter proteins in ZG membranes (aquaporins, vacuolar-type H + -ATPase, zinc influx transporter SLC30A2). The evidence for the K + channels Kv7.1 and Kir6.1, for ClC Cl -channels and the vesicular nucleotide transporter SLC17A9 in ZG is less strong. To better understand the function of these proteins in the secretory pathway further studies are needed. Introductory RemarksA review on the topic of pancreatic zymogen granule (ZG) channels and transporters and their function is timely as the last exhaustive review appeared in 2002 (107) and is manageable because of the limited number of publications that had been published in the 12 years since then. These circumstances have allowed me to carry out an in-depth and critical analysis of the published data. The advent of the post-genomic era had raised hopes that -similar to other areas of cell biology -a large number of ZG transport proteins would be identified and their role in pancreatic secretion would be elucidated. Indeed, recent studies have combined functional and molecular approaches to characterize ZG channels and transporters and their role in pancreas physiology. Yet, the fact that only a very limited number of studies have been published in this area of research is surprising as there have been tremendous developments of knowledge and methodologies available to investigate the molecular and cellular biology and physiology of the pancreas (122).

show abstract

Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis

Cited by 55 publications

References 30 publications

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

Channels and Transporters in Zymogen Granule Membranes and their Role in Granule Function: Recent Progress and a Critical Assessment

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