Angiotensin II Type 2 Receptor Is Critical for the Development of Human Fetal Pancreatic Progenitor Cells into Islet‐like Cell Clusters and Their Potential for Transplantation

Leung, Ka-Cheong; Liang, Juan Boo; Ting, Man; Leung, Po Sing

doi:10.1002/stem.1008

Cited by 25 publications

(35 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the highest AT 2 R density observed in the 1-day neonate pancreas suggests a potential involvement of this receptor in islet growth and development. Indeed, the AT 2 R has been recently demonstrated to play a crucial role in the development of fetal pancreatic progenitor cells into islet-like cell clusters in the human embryo (23).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

Shao

Zucker

Gao

2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

In the present study, we evaluated the relative abundance of angiotensin type 2 receptor (AT2R) protein in various tissues of adult rats. We found that pancreatic islets expressed the highest AT2R protein compared with all other tissues. Accordingly, we then determined the functional significance of AT2R in the endocrine pancreas in in vivo and in vitro experiments by using angiotensin II (ANG II) alone, losartan (Los; AT1R antagonist), compound 21 (C21; AT2R agonist), and PD-123319 (PD; AT2R antagonist). Experiments carried out in rats indicated that, 1) ANG II treatment significantly increased plasma insulin concentration (1.51 Ϯ 0.20 vs. 0.82 Ϯ 0.14 ng/ml, n ϭ 7, P Ͻ 0.05) in the fed state. This insulinotropic effect was further augmented by combined treatment with ANG II ϩ Los (2.31 Ϯ 0.25 ng/ml, n ϭ 7, P Ͻ 0.01). C21 also elevated insulin levels (2.13 Ϯ 0.20 ng/ml, n ϭ 7, P Ͻ 0.01), which was completely abolished by PD. 2) ANG II impaired glucose tolerance, whereas ANG II ϩ Los or C21 improved this function. 3) All treated rats displayed an enhanced insulin secretory response to a glucose challenge. 4) All treated rats displayed upregulated proinsulin 2 mRNA and insulin protein expression in the pancreas. In in vitro experiments using INS-1E cells and isolated rat islets, we found that AT2R activation significantly improved insulin biosynthesis and secretion. These results suggest that the AT2R functions as an insulinotropic mediator. AT2R and its downstream signaling pathways may be potential therapeutic targets for diabetes. compound 21; insulin production; INS-1E cells AS ONE OF THE PRIMARY ANGIOTENSIN II (ANG II) receptor subtypes, the angiotensin type 2 receptor (AT 2 R) was pharmacologically identified (10, 41) and molecularly cloned (19,27) around 20 years ago. However, a complete understanding of the function of the AT 2 R is still incomplete. Evidence implies that the AT 2 R exerts numerous effects such as vasodilatation, tissue protection, and regeneration (21). These biological actions, however, are rarely observed in intact animals because of the relatively lower expression level of AT 2 R compared with its antagonistic twin, the angiotensin type 1 receptor (AT 1 R), and the absence of an exclusive native ligand to the AT 2 R (13).Another reason that AT 2 R actions are not well appreciated comes from the prevailing concept concerning its ontogeny (13). The AT 2 R has long been considered to express at high levels in the fetus and then dramatically decline within 24 h after birth. As a consequence, the AT 2 R in the adult animal has been believed to be a retrogressive receptor and play a minor regulatory role (5). Recent data from our laboratory, however, documented that this dogma may not be true (42). We found that adult rat (43) and mouse (15) expressed significantly higher AT 2 R protein compared with the fetus and neonate. We believe that these results suggest an important function for the AT 2 R in adulthood (16,17).ANG II has been recently assumed to play a role in the regulation of pancre...

show abstract

Section: Discussionmentioning

confidence: 99%

Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

Shao

Zucker

Gao

2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…Moreover, the existence of local renin-angiotensin systems (RAS) in diverse tissues and organs has become increasingly recognized [27]. Included in these systems is the identification of a local RAS in the adult pancreas, which is involved in the regulation of normal exocrine and endocrine functions [26,28].…”

Section: Perspectivesmentioning

confidence: 99%

Control of rene gene expression

Glenn

Jones

Gross

et al. 2012

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Renin, as part of the renin-angiotensin system, plays a critical role in the regulation of blood pressure, electrolyte homeostasis, mammalian renal development and progression of fibrotic/hypertrophic diseases. Renin gene transcription is subject to complex developmental and tissue-specific regulation. Initial studies using the mouse As4.1 cell line, which has many characteristics of the renin-expressing juxtaglomerular cells of the kidney, have identified a proximal promoter region (−197 to −50 bp) and an enhancer (−2866 to −2625 bp) upstream of the Ren-1c gene, which are critical for renin gene expression. The proximal promoter region contains several transcription factor-binding sites including a binding site for the products of the developmental control genes Hox. The enhancer consists of at least 11 transcription factor-binding sites and is responsive to various signal transduction pathways including cAMP, retinoic acid, endothelin-1, and cytokines, all of which are known to alter renin mRNA levels. Furthermore, in vivo models have validated several of these key components found within the proximal promoter region and the enhancer as well as other key sites necessary for renin gene transcription.

show abstract

“…Notably, in support of this interpretation some highly intriguing results have very recently been reported by Leung and colleagues in their studies of human pancreatic progenitor cells and their differentiation to islet cells during in vitro culture (6). They observe highly regulated expression of various components of the renin-angiotensin system (RAS) throughout the progenitor cell differentiation process.…”

Section: Discussionmentioning

confidence: 54%

“…For example multiple lines of evidence have supported renin expression in the rat pancreas (7), and (pro)renin has been localized to both endothelial cells of pancreatic vasculature as well as beta cells of the human pancreas islets (8). More recently, highly intriguing in vitro studies have detected renin and its substrate, angiotenginogen, in early stage differentiating islet cells but not in undifferentiated progenitor cells (6). …”

Section: Introductionmentioning

confidence: 99%

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

et al. 2013

View full text Add to dashboard Cite

Efforts to model human pancreatic neuroendocrine tumors (PanNET) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene while classically associated with expression in the kidney is also expressed in many other extra-renal tissues including the pancreas. To induce tumorigenesis within renin specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon, furthermore an increased level of glucagon is found in the serum identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to lymph nodes and liver, mimicking human disease and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying co-operating mutations that are necessary for progression of disease.

show abstract

Angiotensin II Type 2 Receptor Is Critical for the Development of Human Fetal Pancreatic Progenitor Cells into Islet‐like Cell Clusters and Their Potential for Transplantation

Cited by 25 publications

References 51 publications

Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

Control of rene gene expression

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

Contact Info

Product

Resources

About