Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine

Weinberg, Joel M.; Venkatachalam, Manjeri A.

doi:10.1172/jci60957

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Interestingly, LPS administration significantly decreased the urinary excretion of adenosine [placebo: 77 (50-82) pg adenosine 10 μg À1 creatinine, LPS: 17 (6-33) pg adenosine 10 μg À1 creatinine; P < 0.01], without affecting the excretion of cAMP, ATP, ADP and AMP (data not shown). This may suggest translocation of adenosine to the proximal tubule cells where it is taken up by equilibrative nucleoside transporter-1, thereby restoring intracellular ATP levels (Grenz et al, 2012;Weinberg and Venkatachalam, 2012). RecAP treatment had no effect on adenosine receptor gene expression (Table 2), or on urinary adenosine excretion [LPS + recAP: 11 (5-32) pg adenosine 10 μg À1 creatinine; P < 0.01 compared with placebo] compared with LPS alone.…”

Section: Figurementioning

confidence: 99%

Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate

Peters

Geraci

Heemskerk

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSERecently, two phase-II trials demonstrated improved renal function in critically ill patients with sepsis-associated acute kidney injury treated with the enzyme alkaline phosphatase. Here, we elucidated the dual active effect on renal protection of alkaline phosphatase. EXPERIMENTAL APPROACHThe effect of human recombinant alkaline phosphatase (recAP) on LPS-induced renal injury was studied in Sprague-Dawley rats. Renal function was assessed by transcutaneous measurement of FITC-sinistrin elimination in freely moving, awake rats. The mechanism of action of recAP was further investigated in vitro using conditionally immortalized human proximal tubular epithelial cells (ciPTEC). KEY RESULTSIn vivo, LPS administration significantly prolonged FITC-sinistrin half-life and increased fractional urea excretion, which was prevented by recAP co-administration. Moreover, recAP prevented LPS-induced increase in proximal tubule injury marker, kidney injury molecule-1 expression and excretion. In vitro, LPS-induced production of TNF-α, IL-6 and IL-8 was significantly attenuated by recAP. This effect was linked to dephosphorylation, as enzymatically inactive recAP had no effect on LPS-induced cytokine production. RecAP-mediated protection resulted in increased adenosine levels through dephosphorylation of LPS-induced extracellular ADP and ATP. Also, recAP attenuated LPS-induced increased expression of adenosine A 2A receptor. However, the A 2A receptor antagonist ZM-241385 did not diminish the effects of recAP. CONCLUSIONS AND IMPLICATIONSThese results indicate that the ability of recAP to reduce renal inflammation may account for the beneficial effect observed in septic acute kidney injury patients, and that dephosphorylation of ATP and LPS are responsible for this protective effect.Abbreviations AKI, acute kidney injury; ciPTEC, conditionally immortalized proximal tubular epithelial cells; dLPS, detoxified LPS; IAP, intestinal alkaline phosphatase; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; PBMCs, peripheral blood mononuclear cells; PFA, paraformaldehyde; recAP, human recombinant alkaline phosphatase; TLR4, toll-like receptor 4

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Section: Figurementioning

confidence: 99%

Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate

Peters

Geraci

Heemskerk

et al. 2015

British J Pharmacology

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“…Grenz and colleagues demonstrated how adenosine provides protection against ischemic AKI in mouse models by preserving peritubular capillary blood flow during reperfusion. These authors showed that adenosine activation of endothelial Adora2b results in less tissue hypoxia and improved reperfusion [38, 44]. …”

Section: Kidney Microvasculature and Akimentioning

confidence: 99%

The multifaceted role of the renal microvasculature during acute kidney injury

Maringer

Sims‐Lucas

2015

Pediatr Nephrol

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Pediatric acute kidney injury (AKI) represents a complex disease process for clinicians as it is multifactorial in cause and only limited treatment or preventatives are available. The renal microvasculature has recently been implicated in AKI as a strong therapeutic candidate involved in both injury and recovery. Significant progress has been made in the ability to study the renal microvasculature following ischemic AKI and its role in repair. Advances have also been made in elucidating cell–cell interactions and the molecular mechanisms involved in these interactions. The ability of the kidney to repair post AKI is closely linked to alterations in hypoxia, and these studies are elucidated in this review. Injury to the microvasculature following AKI plays an integral role in mediating the inflammatory response, thereby complicating potential therapeutics. However, recent work with experimental animal models suggests that the endothelium and its cellular and molecular interactions are attractive targets to prevent injury or hasten repair following AKI. Here, we review the cellular and molecular mechanisms of the renal endothelium in AKI, as well as repair and recovery, and potential therapeutics to prevent or ameliorate injury and hasten repair.

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“…This may be seen in a number of acute clinical scenarios, including hemorrhage and endotoxaemia. Adenosine signaling mediates alterations in regional renal blood flow, preserving bioenergetics and cellular structure (Weinberg and Venkatachalam, 2012). …”

Section: Inflammatory Renal Diseasesmentioning

confidence: 99%

Purinergic signaling in inflammatory renal disease

Arulkumaran¹,

Turner²,

Sixma³

et al. 2013

Front. Physiol.

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Extracellular purines have a role in renal physiology and adaption to inflammation. However, inflammatory renal disease may be mediated by extracellular purines, resulting in renal injury. The role of purinergic signaling is dependent on the concentrations of extracellular purines. Low basal levels of purines are important in normal homeostasis and growth. Concentrations of extracellular purines are significantly elevated during inflammation and mediate either an adaptive role or propagate local inflammation. Adenosine signaling mediates alterations in regional renal blood flow by regulation of the renal microcirculation, tubulo-glomerular feedback, and tubular transport of sodium and water. Increased extracellular ATP and renal P2 receptor-mediated inflammation are associated with various renal diseases, including hypertension, diabetic nephropathy, and glomerulonephritis. Experimental data suggests P2 receptor deficiency or receptor antagonism is associated with amelioration of antibody-mediated nephritis, suggesting a pathogenic (rather than adaptive) role of purinergic signaling. We discuss the role of extracellular nucleotides in adaptation to ischemic renal injury and in the pathogenesis of inflammatory renal disease.

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Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine

Cited by 8 publications

References 25 publications

Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate

Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate

The multifaceted role of the renal microvasculature during acute kidney injury

Purinergic signaling in inflammatory renal disease

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