AP214, an analogue of α-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality

Doi, Kent; Hu, Xiaobang; Yuen, Peter S.T.; Leelahavanichkul, Asada; Yasuda, Hideo; Kim, Soo Mi; Schnermann, Jürgen; Jonassen, Thomas E. N.; Frøkiær, Jørgen; Nielsén, Sören; Star, Robert A.

doi:10.1038/ki.2008.97

Cited by 104 publications

(92 citation statements)

References 55 publications

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“…These results name, for the first time, MC peptides with the group of proresolving mediators. We speculate that this effect can be relevant to the tissue-protective properties of AP214 19 and other MC agonists. 50 In all our settings, these proresolving effects require MC 3 expression.…”

Section: Discussionmentioning

confidence: 86%

“…AP214 displays tissue-protective effects against renal postreperfusion injury, 19,20 but the mechanisms behind these tissue-protective actions have not been elucidated. Besides studying the anti-inflammatory and anticytokine effects of AP214 in mice and in cells bearing inactive MC 1 or nullified for MC 3 , we describe the proresolving nature of AP214 on the process of phagocytosis and efferocytosis, a new aspect of MC-based therapy.…”

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confidence: 99%

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The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 g/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC 1 , mutant mice but lost in MC 3 null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1␤, tumor necrosis factor-␣, and IL-6, respectively. Inhibition of IL-1␤ release was retained in MC 1 mutant cells but was lost in MC 3 null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC 3 null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo.

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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“…In a study using the cecal ligation and puncture animal model of sepsis, Doi et al showed marked functional and histologic protection against AKI and reduced mortality when AP214 was administered at 0 and 6 hours before surgery and, most interestingly, even when it was administered up to 6 hours after surgery. 3 In a phase IIa study, AP214 administered in a dose of 600 mg/kg around the time of cardiac surgery decreased the incidence of AKI. 4 In a phase IIb randomized, double-blind, placebo-controlled study for the prevention of AKI in patients undergoing highrisk cardiac surgeries, ABT-719 significantly reduced the composite endpoint consisting of death, need for RRT, or a 25% reduction in renal function during a 90-day postoperative period.…”

Section: A-melanocyte-stimulating Hormonementioning

confidence: 99%

“…1,2 Some critical animal studies demonstrated that a-MSH protects from AKI due to ischemia-reperfusion, 2 nephrotoxins, and sepsis. 1,3 AP214 is an a-MSH analogue with a 10-fold greater affinity for the melanocortin-1 receptor compared with native MSH that has been developed by Action Pharma and licensed recently by Abbott/AbbVie as ABT-719. In a study using the cecal ligation and puncture animal model of sepsis, Doi et al showed marked functional and histologic protection against AKI and reduced mortality when AP214 was administered at 0 and 6 hours before surgery and, most interestingly, even when it was administered up to 6 hours after surgery.…”

Section: A-melanocyte-stimulating Hormonementioning

confidence: 99%

Challenges and Advances in the Treatment of AKI

Kaushal

Shah

2014

Journal of the American Society of Nephrology

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Treating or preventing AKI requires treating or preventing a rise in serum creatinine as well as the immediate and remote clinical consequences associated with AKI. Because a substantial number of patients with AKI progress to ESRD, identifying patients likely to progress and halting progression are important goals for treating AKI. Many therapies for AKI are being developed, including RenalGuard Therapy, which aims to maintain high urine output; a-melanocyte-stimulating hormone, with anti-inflammatory and antiapoptotic activities; alkaline phosphatase, which detoxifies proinflammatory substances; novel, small interfering RNA, directed at p53 activation; THR-184, a peptide agonist of bone morphogenetic proteins; removal of catalytic iron, important in free-radical formation; and cell-based therapies, including mesenchymal stem cells in vivo and renal cell therapy in situ. In this review, we explore what treatment of AKI really means, discuss the emerging therapies, and examine the windows of opportunity for treating AKI. Finally, we provide suggestions for accelerating the pathways toward preventing and treating AKI, such as establishing an AKI network, implementing models of catalytic philanthropy, and directing a small percentage of the Medicare ESRD budget for developing therapies to prevent and treat AKI and halt progression of CKD.

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“…We induced sepsis by CLP surgery with 8-mm cecal ligation, which causes modest sublethal sepsis in normal outbred CD-1 mice. 8 All animals survived until they were killed at 18 h after surgery. CLP surgery in non-nephrectomized mice caused a numerically small, but not significant increase of serum creatinine (sham BNx ϩCLP group).…”

mentioning

confidence: 99%

Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis

Doi¹,

Yuen²,

Eisner³

et al. 2009

Journal of the American Society of Nephrology

333

192

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Serum creatinine is used clinically to detect and evaluate acute kidney injury (AKI) and chronic kidney disease (CKD), 1,2 although the limitations of serum creatinine for the early detection and accurate estimation of renal injury are widely known. In AKI, serum creatinine does not accurately reflect the GFR because the patient is not in steady state. 3 Furthermore, serum creatinine is also influenced by tubular creatinine secretion and by nonrenal factors such as muscle mass, liver function, and nonrenal (gastrointestinal) elimination.Sepsis remains a serious problem in critically ill patients, and mortality from sepsis is increased dramatically when complicated by AKI; therefore, early detection and accurate evaluation of AKI is important in patients with sepsis. We modified the cecal ligation and puncture (CLP) mouse sepsis model to make it more clinically relevant, and our model developed sepsis-induced AKI. 4 -6 We found that serum creatinine increased to a lesser extent in CLP (approximately 0.5 mg/dl) than ischemia/reperfusion or cisplatin administration (Ͼ1 mg/dl) within 24 h of injury. To explore nonrenal factors that might account for this disparity, we used bilateral nephrectomy (BNx), a technique used recently by others to study the contribution of the kidney to cytokine metabolism and acute lung injury. 7 First, we evaluated sepsis in bilaterally nephrectomized mice. We induced sepsis by CLP surgery with 8-mm cecal ligation, which causes modest sublethal sepsis in normal outbred CD-1 mice. 8 All animals survived until they were killed at 18 h after surgery. CLP surgery in non-nephrectomized mice caused a numerically small, but not significant increase of serum creatinine (sham BNx ϩCLP group). As expected, we found large increases of serum creatinine in the BNxϩsham CLP group; however, induction of sepsis at the time of BNx significantly decreased serum creatinine (BNxϩCLP group) compared with nonseptic BNx alone (BNxϩsham CLP group; Figure 1A), raising doubt about whether serum creatinine accurately reflects impaired kidney function during sepsis. In contrast, nonrenal organ injury markers (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]) and serum TNF-␣ were higher in the BNxϩCLP group than in the BNxϩsham CLP group, confirming the presence of severe sepsis (Figure 1, ABSTRACTAlthough diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-␣. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decrease...

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AP214, an analogue of α-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality

Cited by 104 publications

References 55 publications

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Challenges and Advances in the Treatment of AKI

Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis

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