New role for the (pro)renin receptor in T-cell development

Geisberger, Sabrina; Maschke, Ulrike; Gebhardt, M.; Kleinewietfeld, Markus; Manzel, Arndt; Linker, Ralf A.; Chidgey, Ann Patricia; Dechend, Ralf; Nguyen, Geneviève; Daumke, Oliver; Müller, Dominik N.; Wright, Mark D.; Binger, Katrina J.

doi:10.1182/blood-2015-03-635292

Cited by 21 publications

(14 citation statements)

References 20 publications

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“…PRR is a new component of renin angiotensin system (RAS) and has high affinity with prorenin and renin resulting in cleavage of angiotensinogen and signaling through the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways [7]. Moreover, PRR is mainly expressed in kidney, heart, pancreas, brain, blood vessels, macrophages, T cells and granulocytes [8–10]. Although several studies have shown that PRR is involved in renal and heart pathophysiology such as diabetic nephropathy, kidney ischemic, cardiac fibrosis [11, 12], the role in pancreas remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis

et al. 2016

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Recent studies have implicated the prorenin receptor (PRR) is associated with pancreatic tumorigenesis. We therefore investigated the role of PRR in pancreatic tumorigenesis and assessed whether PRR can serve as a target for imaging diagnosis at early stages of PDAC. Here we show that aberrant expression of PRR in premalignant PanIN lesions, and human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells. Interestingly, PRR expression was positively associated with PDAC progression. Moreover, overexpression of human PRR resulted in increased cell proliferation and decreased apoptosis, while knockdown of human PRR caused decreased cell proliferation and enhanced apoptosis in pancreatic cancer cells. We also observed that overexpression of human PRR enhanced MAPK and PI3K/Akt signaling pathways in PDAC cells, while knockdown of human PRR suppressed both of pathways. The confocal imaging analysis showed that human PRR was highly expressed in Panc-1, ASPC, and Miapaca cells, whereas BXPC-3, and HPAC cells had a significantly lower fluorescent signals. Consistently, the single-photon emission computed tomography (SPET/CT) showed that the uptake of anti-PRR labelled with 125I was higher in Panc-1 and ASPC tumors-bearing mice after 96 hours injection. Importantly, tumors in pancreas of Pdx1-cre; LSL-KrasG12D mice had a significant increased PRR expression and accumulation of radioactivity at 96 h after injection. These data suggest that 125I-anti-PRR can detect the orthotopic tumors in Pdx1-cre; LSL-KrasG12D mice. Therefore, anti-PRR labelled with 125I is a promising radiotracer for imaging diagnosis at early stages of pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis

et al. 2016

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“…In the years since its discovery, much effort has been directed toward the characterization of signaling pathways that are "controlled" by Atp6ap2. These include Wnt (25)(26)(27) and promyelocytic leukemia zinc finger (PLZF) (39) signaling, despite a lack of similarity between the respective in vivo models (21), and that employed concentrations of its "ligands" renin and (pro)renin were several orders of magnitude above circulating levels (16). Abnormal vacuolar phenotypes are evident upon conditional Atp6ap2 knockout from cardiomyocytes (19), podocytes (18,20), and hepatocytes (24).…”

Section: Discussionmentioning

confidence: 99%

“…Atp6ap2 was initially misnamed as the (pro)renin receptor (PRR), as it was thought to bind renin and contribute to the pathology of hypertension (15,16). Atp6ap2 has since been shown to be essential for cellular homeostasis in mice, as its knockout is embryonic lethal (17), while conditional deletion impairs the function of a variety of cell types (18)(19)(20)(21)(22)(23)(24). Its role in Drosophila and Xenopus development is also established (25)(26)(27).…”

Section: Significancementioning

confidence: 99%

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells

Binger

Neukam

Tattikota

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.

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“…39,40 Within the immune system, the PRR pathway is active in human monocytes and is required in T lymphocytes for their acquisition of peripheral T cell markers including CD4 and CD8 during thymic education. 41,42 Moreover, the PRR is expressed on both macrophages and T cells infiltrating the glomerulus during human crescentic GN, and renin-mediated induction of IL-6 and cyclooxygenase-2 in human mononuclear cells requires extracellular signal-regulated kinase 1/2 phosphorylation but not angiotensin receptor ligation. 43 These data support a new paradigm in which RAS components other than the effector molecule Ang II modulate inflammation in the target organ.…”

Section: Renin/proreninmentioning

confidence: 99%

Immunologic Effects of the Renin-Angiotensin System

Crowley

Rudemiller

2017

JASN

134

131

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Inappropriate activation of the renin-angiotensin system (RAS) exacerbates renal and vascular injury. Accordingly, treatment with global RAS antagonists attenuates cardiovascular risk and slows the progression of proteinuric kidney disease. By reducing BP, RAS inhibitors limit secondary immune activation responding to hemodynamic injury in the target organ. However, RAS activation in hematopoietic cells has immunologic effects that diverge from those of RAS stimulation in the kidney and vasculature. In preclinical studies, activating type 1 angiotensin (AT) receptors in T lymphocytes and myeloid cells blunts the polarization of these cells toward proinflammatory phenotypes, protecting the kidney from hypertensive injury and fibrosis. These endogenous functions of immune AT receptors temper the pathogenic actions of renal and vascular AT receptors during hypertension. By counteracting the effects of AT receptor stimulation in the target organ, exogenous administration of AT receptor agonists or angiotensin 1-7 analogs may similarly limit inflammatory injury to the heart and kidney. Moreover, although angiotensin II is the classic effector molecule of the RAS, several RAS enzymes affect immune homeostasis independently of canonic angiotensin II generation. Thus, as reviewed here, multiple components of the RAS signaling cascade influence inflammatory cell phenotype and function with unpredictable and context-specific effects on innate and adaptive immunity.

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New role for the (pro)renin receptor in T-cell development

Abstract: Key Points PRR deletion in T cells drastically reduces the number of peripheral and thymic CD3+ T cells. We identify multiple stages of thymocyte development that require PRR expression.

Cited by 21 publications

References 20 publications

Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis

Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells

Immunologic Effects of the Renin-Angiotensin System

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