Renal Intercalated Cells Sense and Mediate Inflammation via the P2Y14 Receptor

Azroyan, Anie; Cortez-Retamozo, Virna; Bouley, Richard; Liberman, Rachel; Ruan, Ye Chun; Kiselev, Evgeny; Jacobson, Kenneth A.; Pittet, Mikaël J.; Brown, Dennis; Breton, Sylvie

doi:10.1371/journal.pone.0121419

Cited by 74 publications

(97 citation statements)

References 76 publications

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“…We recently showed that the adenosine receptors ADORA2A and ADORA2B, located in the apical membrane of the collecting duct ICs, stimulate proton secretion via activation of the cAMP/PKA pathway [20]. In this review article, we describe how another member of the purinergic family, the proinflammatory receptor P2Y 14 , mediates renal inflammation via ICs [1], and suggest how this might be applicable to the diagnosis and treatment of AKI.…”

Section: Purinergic Signaling In the Kidneymentioning

confidence: 98%

“…In contrast to most nucleotides, which are rapidly degraded by ectonucleotidases after their release, UDP-glucose resists hydrolysis by these enzymes [25]. P2Y 14 is an inflammatory mediator that is expressed in immune cells [26][27][28], the brain, gastrointestinal tract, kidney, and lungs [1,21,29]. Patients with cystic fibrosis and asthma have elevated concentrations of UDP-glucose in their lungs [30,31], and P2Y 14 activation by UDP-glucose in airway epithelial cells leads to interleukin 8 secretion and an inflammatory response [32].…”

Section: Identification Of the P2y 14 Receptor In Collecting Duct Icsmentioning

confidence: 99%

“…Our recent screening of the proteome and transcriptome of ICs unexpectedly revealed very high expression levels of the purinergic receptor P2Y 14 [1]. ICs were isolated by fluorescence activated cell sorting from previously characterized transgenic mice that express enhanced green fluorescent protein (EGFP) specifically in these cells (B1-EGFP mice) [35]; no expression was detected in all other renal cell types [1].…”

Section: Identification Of the P2y 14 Receptor In Collecting Duct Icsmentioning

confidence: 99%

“…ICs were isolated by fluorescence activated cell sorting from previously characterized transgenic mice that express enhanced green fluorescent protein (EGFP) specifically in these cells (B1-EGFP mice) [35]; no expression was detected in all other renal cell types [1]. In addition, RNA sequencing of isolated EGFP ICs identified P2Y 14 as one of the most expressed genes in these cells, while single cell RNA sequencing showed specific expression of P2Y 14 in type A ICs [36].…”

Section: Identification Of the P2y 14 Receptor In Collecting Duct Icsmentioning

confidence: 99%

“…Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. in the kidney medulla [1]. This resulted from our identification of high expression of the proinflammatory uridine diphosphate (UDP)-glucose receptor P2Y 14 in A-ICs.…”

Section: Introductionmentioning

confidence: 99%

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Novel Proinflammatory Function of Renal Intercalated Cells

Breton

Brown²

2018

Ann Nutr Metab

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Background: Serious and often fatal acute kidney injury (AKI) is frequently seen after major surgery, local and remote organ damage, and sepsis. It is associated with uncontrolled inflammation, and is usually diagnosed only after the kidneys have gone through significant and often irreversible damage. Summary: During our work involving another type of kidney disease that leads to acid-base disorders of the blood, we unexpectedly found high levels of a protein called the P2Y₁₄ “purinergic” receptor, in specialized kidney epithelial cells called intercalated cells (ICs). These cells are responsible for maintaining whole body acid-base balance by regulating the secretion of excess protons into the urine, which normalizes blood pH. However, it turns out that the P2Y₁₄ receptor in these cells responds to a molecule called uridine diphosphate (UDP)-glucose, which is a danger signal released by damaged cells anywhere in the body. When UDP-glucose reaches the kidney, it stimulates ICs to produce chemoattractant cytokines; this results in renal inflammation and contributes to the onset of AKI. Key Message: Thus, our work now points to ICs as key mediators of renal inflammation and AKI, following surgery and/or damage to remote organs, sepsis, and also local insults to the kidney itself. The link between the proton secreting ICs of the kidney and AKI is an example of how a fundamental research project with a defined aim, in this case understanding acid-base homeostasis, can lead to a novel observation that has unexpected but major implications in another area of human health.

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Section: Purinergic Signaling In the Kidneymentioning

confidence: 98%

Section: Identification Of the P2y 14 Receptor In Collecting Duct Icsmentioning

confidence: 99%

Section: Identification Of the P2y 14 Receptor In Collecting Duct Icsmentioning

confidence: 99%

Section: Identification Of the P2y 14 Receptor In Collecting Duct Icsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Proinflammatory Function of Renal Intercalated Cells

Breton

Brown²

2018

Ann Nutr Metab

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P2Y₁₄ receptor is functionally expressed in satellite glial cells and mediates interleukin‐1β and chemokine CCL2 secretion

Lin

Liu

Zhang

et al. 2019

Journal Cellular Physiology

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Satellite glial cells (SGCs) activation in the trigeminal ganglia (TG) is critical in various abnormal orofacial sensation in nerve injury and inflammatory conditions. SGCs express several subtypes of P2 purinergic receptors contributing to the initiation and maintenance of neuropathic pain. The P2Y 14 receptor, a G-protein-coupled receptor activated by uridine diphosphate (UDP)-glucose and other UDP sugars, mediates various physiologic events such as immune, inflammation, and pain. However, the expression, distribution, and function of P2Y 14 receptor in SGCs remains largely unexplored. Our study reported the expression and functional identification of P2Y 14 receptor in SGCs. SGCs were isolated from TG of rat, and the P2Y 14 receptor expression was examined using immunofluorescence technique. Cell proliferation and viability were examined via cell counting kit-8 experiment. Immunofluorescence demonstrated the presence of P2Y 14 receptor in SGCs. Immunofluorescence and western blot showed that UDP-glucose treatment upregulated glial fibrillary acid protein, a common marker for glial activation. Extracellular UDP-glucose enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, which were both abolished by the P2Y 14 receptor inhibitor (PPTN). Furthermore, quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay demonstrated that extracellular UDPglucose significantly enhanced interleukin-1β (IL-1β) and chemokine CCL2 (CCL2) release, which was abolished by PPTN and significantly decreased by inhibitors of MEK/ERK (U0126) and p38 (SB202190). Our findings directly proved the functional presence of P2Y 14 receptor in SGCs. It was also verified that P2Y 14 receptor activation was involved in activating SGCs, phosphorylating MAPKs, and promoting the secretion of IL-1β and CCL2 via ERK and p38 pathway.

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Chemogenetic stimulation of the G_i pathway in astrocytes suppresses neuroinflammation

Kim

Rahman

Lee

et al. 2021

Pharmacology Res & Perspec

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Engineered G protein‐coupled receptors (GPCRs) are commonly used in chemogenetics as designer receptors exclusively activated by designer drugs (DREADDs). Although several GPCRs have been studied in astrocytes using a chemogenetic approach, the functional role of the astrocytic Gi pathway is not clear, as the literature is conflicting depending on the brain regions or behaviors investigated. In this study, we evaluated the role of the astrocytic Gi pathway in neuroinflammation using a Gi‐coupled DREADD (hM4Di). Gi‐DREADD was expressed in hippocampal astrocytes of a lipopolysaccharide (LPS)‐induced neuroinflammation mouse model using adeno‐associated viruses. We found that astrocyte Gi‐DREADD stimulation using clozapine N‐oxide (CNO) inhibits neuroinflammation, as characterized by decreased levels of proinflammatory cytokines, glial activation, and cognitive impairment in mice. Subsequent experiments using primary astrocyte cultures revealed that Gi‐DREADD stimulation significantly downregulated LPS‐induced expression of Nos2 mRNA and nitric oxide production. Similarly, in vitro calcium imaging showed that activation of the astrocytic Gi pathway attenuated intracellular calcium transients triggered by LPS treatment, suggesting a positive correlation between enhanced calcium transients and the inflammatory phenotype of astrocytes observed in the inflamed brain. Taken together, our results indicate that the astrocytic Gi pathway plays an inhibitory role in neuroinflammation, providing an opportunity to identify potential cellular and molecular targets to control neuroinflammation.

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Renal Intercalated Cells Sense and Mediate Inflammation via the P2Y14 Receptor

Cited by 74 publications

References 76 publications

Novel Proinflammatory Function of Renal Intercalated Cells

Novel Proinflammatory Function of Renal Intercalated Cells

P2Y₁₄ receptor is functionally expressed in satellite glial cells and mediates interleukin‐1β and chemokine CCL2 secretion

Chemogenetic stimulation of the G_i pathway in astrocytes suppresses neuroinflammation

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Renal Intercalated Cells Sense and Mediate Inflammation via the P2Y14 Receptor

Cited by 74 publications

References 76 publications

Novel Proinflammatory Function of Renal Intercalated Cells

Novel Proinflammatory Function of Renal Intercalated Cells

P2Y14 receptor is functionally expressed in satellite glial cells and mediates interleukin‐1β and chemokine CCL2 secretion

Chemogenetic stimulation of the Gi pathway in astrocytes suppresses neuroinflammation

Contact Info

Product

Resources

About

P2Y₁₄ receptor is functionally expressed in satellite glial cells and mediates interleukin‐1β and chemokine CCL2 secretion

Chemogenetic stimulation of the G_i pathway in astrocytes suppresses neuroinflammation