Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice

Kim, Minjae; Park, Sang Won; Kim, Mihwa; Chen, Sean W. C.; Gerthoffer, William T.; D’Agati, Vivette D.; Lee, H. Thomas

doi:10.1152/ajprenal.00194.2010

Cited by 65 publications

(57 citation statements)

References 45 publications

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“…23,51,52 To test the effects of specific S1P receptor subtype antagonists on renal function after IR injury, we treated mice with intraperitoneal W146, JTE-013, or CAY10444, selective inhibitors for S1P 1 R, S1P 2 R, and S1P 3 R, respectively (0.01-0.1 mg/kg), 10 minutes before and 30 minutes after renal ischemia or sham operation. We also tested whether a single injection of JTE-013 could also provide renal protection after IR injury.…”

Section: Murine Model Of Renal Ir Injurymentioning

confidence: 99%

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Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Park

Kim²,

Brown³

et al. 2012

Journal of the American Society of Nephrology

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Activation of the sphingosine 1-phosphate receptor 1 (S1P 1 R) protects against renal ischemia-reperfusion (IR) injury and inflammation, but the role of other members of this receptor family in modulating renal IR injury is unknown. We found that a selective S1P 2 R antagonist protected against renal IR injury in a dosedependent manner. Consistent with this observation, both S1P 2 R-deficient mice and wild-type mice treated with S1P 2 R small interfering RNA had reduced renal injury after IR. In contrast, a selective S1P 2 R agonist exacerbated renal IR injury. The S1P 2 R antagonist increased sphingosine kinase-1 (SK1) expression via Rho kinase signaling in renal proximal tubules; the S1P 2 R agonist decreased SK1. S1P 2 R antagonism failed to protect the kidneys of SK1-deficient mice or wild-type mice pretreated with an SK1 inhibitor or an S1P 1 R antagonist, suggesting that the renoprotection conferred by S1P 2 R antagonism results from pathways involving activation of S1P 1 R by SK1. In cultured human proximal tubule (HK-2) cells, the S1P 2 R antagonist selectively upregulated SK1 and attenuated both H 2 O 2 -induced necrosis and TNF-a/cycloheximideinduced apoptosis; the S1P 2 R agonist had the opposite effects. In addition, increased nuclear hypoxia inducible factor-1a was critical in mediating the renoprotective effects of S1P 2 R inhibition. Finally, induction of SK1 and S1P 2 R in response to renal IR and S1P 2 R antagonism occurred selectively in renal proximal tubule cells but not in renal endothelial cells. Taken together, these data suggest that S1P 2 R may be a therapeutic target to attenuate the effects of renal IR injury. AKI is a major clinical complication with high mortality, morbidity, and cost. 1,2 Renal ischemia and reperfusion (IR) injury is a major cause of perioperative AKI for patients undergoing surgery involving the kidney, liver, or aorta. 3,4 Unfortunately, the severity and incidence of AKI have been increasing, without any improvements in therapy or patient survival over the past 50 years. 5 The incidence of renal dysfunction in high-risk patients after major cardiovascular, hepatobiliary, or aortic surgery approaches 70%-80%. 3,4,6 Despite continued research searching for renal protective agents, there are no proven therapies to reduce AKI in the perioperative setting 1,7 Sphingolipids are pleiotropic regulators of kidney physiology that modulate diverse pathways of cell death, including necrosis, apoptosis, inflammation, and immunity. 8,9 In particular, phosphorylation of sphingosine by sphingosine kinases (SK1 and SK2) leads to the formation of sphingosine 1-phosphate (S1P), a lysophospholipid targeting G-protein-coupled receptor that has diverse extracellular as well as intracellular effects. 9 Of five G-protein-coupled receptors for S1P, activation of endothelial S1P 1 R receptor (S1P 1 R) reduces permeability and maintains the integrity of the vascular endothelial cell

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Section: Murine Model Of Renal Ir Injurymentioning

confidence: 99%

“…An established grading scale of necrotic injury (Renal Injury Score, 0-4) to the proximal tubules was used for the histopathologic assessment of IR-induced damage, as outlined by Jablonski and colleagues 19 and as described previously in our studies. 23,52 Detection of Renal Tubular Apoptosis…”

Section: Histologic Detection Of Necrosismentioning

confidence: 99%

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Park

Kim²,

Brown³

et al. 2012

Journal of the American Society of Nephrology

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“…2, 37) to 30 min of renal IR as described previously (22,25). To test the renal protective effects of IL-11, we pretreated mice with saline (vehicle for HR IL-11), PEG (vehicle for PEGylated IL-11), HR IL-11 (0.1-1 mg/kg ip), or long-acting PEGylated IL-11 (0.1-1 mg/kg ip) 10 min before renal ischemia or sham operation.…”

Section: Methodsmentioning

confidence: 99%

Interleukin-11 protects against renal ischemia and reperfusion injury

Lee

Park

Kim

et al. 2012

American Journal of Physiology-Renal Physiology

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“…36,37 Renalase KO or WT mice (C57BL/6 from Harlan Laboratories, Indianapolis, IN) were subjected to sham operation or to 20 minutes (moderate) or 30 minutes (severe) of renal ischemia and 24 hours of reperfusion. To test the renal protective effects of recombinant human renalase, we pretreated mice with saline (vehicle) or with recombinant renalase (0.5, 1.5, or 4.5 mg/kg, subcutaneously) 10 minutes before 30 minutes of renal ischemia.…”

Section: Murine Model Of Renal Ir Injurymentioning

confidence: 99%

Renalase Protects against Ischemic AKI

Lee¹,

Kim²,

Kim³

et al. 2013

Journal of the American Society of Nephrology

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Elevated levels of plasma catecholamines accompany ischemic AKI, possibly contributing the inflammatory response. Renalase, an amine oxidase secreted by the proximal tubule, degrades circulating catecholamines and reduces myocardial necrosis, suggesting that it may protect against renal ischemia reperfusion injury. Here, mice subjected to renal ischemia reperfusion injury had significantly lower levels of renalase in the plasma and kidney compared with sham-operated mice. Consistent with this, plasma NE levels increased significantly after renal ischemia reperfusion injury. Furthermore, renal tubular inflammation, necrosis, and apoptosis were more severe and plasma catecholamine levels were higher in renalasedeficient mice subjected to renal ischemia reperfusion compared with wild-type mice. Administration of recombinant human renalase reduced plasma catecholamine levels and ameliorated ischemic AKI in wildtype mice. Taken together, these data suggest that renalase protects against ischemic AKI by reducing renal tubular necrosis, apoptosis, and inflammation, and that plasma renalase might be a biomarker for AKI. Recombinant renalase therapy may have potential for the prevention and treatment of AKI.

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Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice

Cited by 65 publications

References 45 publications

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Interleukin-11 protects against renal ischemia and reperfusion injury

Renalase Protects against Ischemic AKI

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