Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

Gupta, Akanksha; Berg, David T.; Gerlitz, Bruce; Sharma, Ganesh R.; Syed, Samreen K.; Richardson, Mark A.; Sandusky, George E.; Heuer, Josef G.; Galbreath, Elizabeth; Grinnell, Brian W.

doi:10.1681/asn.2006101167

Cited by 50 publications

(55 citation statements)

References 55 publications

(52 reference statements)

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“…We observed a nuclear pattern of positive signals in tubular cells as had already been described by others. [24][25][26] The expression was increased in Gly-AKI ( Figure 3B) and significantly exacerbated by silymarin treatment ( Figure 3C). The quantitative analysis confirmed statistically significant increase in the expression of cleaved caspase-3 in Gly-AKI + silymarin ( Figure 3D).…”

Section: Effects Of Silymarin On Renal Function and Tubular Injury Inmentioning

confidence: 96%

Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

2010

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Background/aims: Silymarin is an herbal extract with antioxidant properties that can reduce oxidative stressmediated injuries in murine models of liver, heart, and kidney diseases. Silymarin can also increase p53-mediated cellular apoptosis in vitro. We tested the effect of silymarin administration before glycerol-induced acute kidney injury (Gly-AKI) in rats. Methods: Renal function, tubular injury, oxidative stress, leukocytes infiltration, and renal expression of apoptosis regulating proteins (p53, p-p53, Bax, Bcl-2, survivin, and cleaved caspase-3) were evaluated 6 or 24 h after glycerol. Results: Silymarin exacerbated the renal impairment and tubular apoptosis but had no effect on tubular necrosis or renal leukocytes infiltration. Renal lipid and DNA peroxidation was increased after glycerol and silymarin did not reduce oxidative stress. Proteins p53, p-p53, and proapoptotic Bax were upregulated in Gly-AKI rats treated with silymarin, whereas anti-apoptotic Bcl-2 was reduced in this group. Cleaved caspase-3 was overexpressed in Gly-AKI rats, particularly when treated with silymarin. Survivin was less expressed in Gly-AKI than in controls, but this deficit was not aggravated by silymarin. Conclusion: The persistence of oxidative stress, inflammatory reaction, and tubular necrosis, as well as exacerbation of p53-mediated tubular apoptosis, led to a more severe renal impairment in Gly-AKI rats treated with silymarin.

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Section: Effects Of Silymarin On Renal Function and Tubular Injury Inmentioning

confidence: 96%

Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

2010

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“…Nevertheless, the criteria used for renal dysfunction in that study (that is, oliguria) are questionable, because oliguria cannot be considered a fully accurate marker of kidney damage. Furthermore, animal studies have suggested a protective effect of APC in sepsis-induced kidney injury (216,217).…”

Section: Therapeutic Implications and Perspectivesmentioning

confidence: 99%

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

Legrand

Mik

Johannes³

et al. 2008

Mol Med

237

169

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Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium-leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways' alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed.

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“…10 Moreover, low levels of PC have been highly associated with renal dysfunction and pathology in models of AKI. 11 During vascular insult, PC becomes activated by the endothelial thrombin-thrombomodulin complex, and the activated protein C (APC) exhibits both antithrombotic and cytoprotective properties. We have previously demonstrated that APC administration protects from renal dysfunction during cecal ligation and puncture and after endotoxin challenge.…”

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confidence: 99%

“…We have previously demonstrated that APC administration protects from renal dysfunction during cecal ligation and puncture and after endotoxin challenge. 11,12 In addition, recombinant human APC [drotrecogin alfa (activated)] has been shown to reduce mortality in patients with severe sepsis at high risk of death. 13 Although the ability of APC to protect from organ injury in vivo is well documented, 11,14,15 the precise mechanism mediating the response has not been ascertained.…”

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confidence: 99%

Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury

Gupta

Gerlitz

Richardson

et al. 2009

Journal of the American Society of Nephrology

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Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney. 20: 267-277, 200920: 267-277, . doi: 10.1681 Acute kidney injury (AKI) leading to renal failure is a devastating disorder, 1 with a prevalence varying from 30 to 50% in the intensive care unit. 2 AKI during sepsis results in significant morbidity, and is an independent risk factor for mortality. 3,4 In patients with severe sepsis or shock, the reported incidence ranges from 23 to 51% 5-7 with mortality as high as 70% versus 45% among patients with AKI alone. 1,8 The pathogenesis of AKI during sepsis involves hemodynamic alterations along with microvascular impairment. 4 Although many factors change during sepsis, suppression of the plasma serine protease, protein C (PC), has been shown to be predictive of early death in sepsis models, 9 and clinically has been associated with early death resulting from refractory shock and multiple organ failure in severe sepsis. 10 Moreover, low levels of PC have been J Am Soc Nephrol

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Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

Cited by 50 publications

References 55 publications

Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury

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