ATP induces PAD4 in renal proximal tubule cells via P2X7 receptor activation to exacerbate ischemic AKI

Rabadi, May M.; Kim, Mihwa; Li, Hongmei; Han, Sang Jun; Choi, Y.-J. A.; D’Agati, Vivette D.; Lee, H. Thomas

doi:10.1152/ajprenal.00364.2017

Cited by 26 publications

(28 citation statements)

References 63 publications

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“…17 Few studies have examined the importance of P2 receptors in AKI; however, inhibition of P2X7R attenuates inflammation and IRI. 18,19 Overall, ATP is implicated in several physiologic and pathologic settings in the kidney.…”

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confidence: 99%

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Jankowski¹,

Perry²,

Medina

et al. 2018

JASN

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Pannexin1 (Panx1), an ATP release channel, is present in most mammalian tissues, but the role of Panx1 in health and disease is not fully understood. Panx1 may serve to modulate AKI; ATP is a precursor to adenosine and may function to block inflammation, or ATP may act as a danger-associated molecular pattern and initiate inflammation. We used pharmacologic and genetic approaches to evaluate the effect of Panx1 on kidney ischemia-reperfusion injury (IRI), a mouse model of AKI. Pharmacologic inhibition of gap junctions, including Panx1, by administration of carbenoxolone protected mice from IRI. Furthermore, global deletion of preserved kidney function and morphology and diminished the expression of proinflammatory molecules after IRI. Analysis of bone marrow chimeric mice revealed that Panx1 expressed on parenchymal cells is necessary for ischemic injury, and both proximal tubule and vascular endothelial tissue-specific knockout mice were protected from IRI. ,-deficient proximal tubule cells released less and retained more ATP under hypoxic stress. Panx1 is involved in regulating ATP release from hypoxic cells, and reducing this ATP release may protect kidneys from AKI.

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confidence: 99%

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Jankowski¹,

Perry²,

Medina

et al. 2018

JASN

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“…Renal IR injury induces protein and mRNA, as well as activity of renal tubular PAD4, and pharmacological inhibition or gene deletion of PAD4 protects kidney from renal IR injury by reducing inflammatory response and apoptosis [80,81]. In additional studies, we demonstrated that ATP induces renal tubular PAD4 via protein kinase C signaling, and PAD4 is the critical mediator of P 2 X 7 -mediated kidney inflammation and injury after renal IR injury because the P 2 X 7 receptor failed to exacerbate ischemic AKI in PAD4 knockout mice [82]. Furthermore, we found that PAD4 preferentially citrullinates inhibitor of κB (IκB) kinase-γ (IKK-γ, also known as NFκB essential modulator or NEMO) over other IKK subunits, IKK-α or IKK-β.…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Mechanisms and therapeutic targets of ischemic acute kidney injury

Han

Lee

2019

Kidney Res Clin Pract

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184

145

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Acute kidney injury (AKI) due to renal ischemia reperfusion (IR) is a major clinical problem without effective therapy and is a significant and frequent cause of morbidity and mortality during the perioperative period. Although the pathophysiology of ischemic AKI is not completely understood, several important mechanisms of renal IR-induced AKI have been studied. Renal ischemia and subsequent reperfusion injury initiates signaling cascades mediating renal cell necrosis, apoptosis, and inflammation, leading to AKI. Better understanding of the molecular and cellular pathophysiological mechanisms underlying ischemic AKI will provide more targeted approach to prevent and treat renal IR injury. In this review, we summarize important mechanisms of ischemic AKI, including renal cell death pathways and the contribution of endothelial cells, epithelial cells, and leukocytes to the inflammatory response during ischemic AKI. Additionally, we provide some updated potential therapeutic targets for the prevention or treatment of ischemic AKI, including Toll-like receptors, adenosine receptors, and peptidylarginine deiminase 4. Finally, we propose mechanisms of ischemic AKI-induced liver, intestine, and kidney dysfunction and systemic inflammation mainly mediated by Paneth cell degranulation as a potential explanation for the high mortality observed with AKI.

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“…Inhibition of purinergic receptors was protective in both ischemic and sepsis-induced AKI (111,112). ATP and selective agonists of the P2X 7 receptor were shown to activate peptidyl arginine deaminase 4 (PAD4) in proximal tubular cells (PTCs) and exacerbate IRI (113). Recently, the P2X 4 receptor was shown to exacerbate ischemic AKI through NLRP3 inflammasome signaling in the renal proximal convoluted tubules (PCTs) (114).…”

Section: Mitochondrial Alarminsmentioning

confidence: 99%

The Yin and Yang of Alarmins in Regulation of Acute Kidney Injury

et al. 2020

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Acute kidney injury (AKI) is a major clinical burden affecting 20 to 50% of hospitalized and intensive care patients. Irrespective of the initiating factors, the immune system plays a major role in amplifying the disease pathogenesis with certain immune cells contributing to renal damage, whereas others offer protection and facilitate recovery. Alarmins are small molecules and proteins that include granulysins, high-mobility group box 1 protein, interleukin (IL)-1α, IL-16, IL-33, heat shock proteins, the Ca ++ binding S100 proteins, adenosine triphosphate, and uric acid. Alarmins are mostly intracellular molecules, and their release to the extracellular milieu signals cellular stress or damage, generally leading to the recruitment of the cells of the immune system. Early studies indicated a proinflammatory role for the alarmins by contributing to immune-system dysregulation and worsening of AKI. However, recent developments demonstrate anti-inflammatory mechanisms of certain alarmins or alarmin-sensing receptors, which may participate in the prevention, resolution, and repair of AKI. This dual function of alarmins is intriguing and has confounded the role of alarmins in AKI. In this study, we review the contribution of various alarmins to the pathogenesis of AKI in experimental and clinical studies. We also analyze the approaches for the therapeutic utilization of alarmins for AKI.

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ATP induces PAD4 in renal proximal tubule cells via P2X7 receptor activation to exacerbate ischemic AKI

Cited by 26 publications

References 63 publications

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Mechanisms and therapeutic targets of ischemic acute kidney injury

The Yin and Yang of Alarmins in Regulation of Acute Kidney Injury

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