Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice

Dear, James W.; Kobayashi, Hisataka; Jo, Sang Kyung; Holly, Mikaela K.; Hu, Xiaobang; Yuen, Peter S.T.; Brechbiel, Martin W.; Star, Robert A.

doi:10.1111/j.1523-1755.2005.00321.x

Cited by 55 publications

(56 citation statements)

References 26 publications

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“…Because volume resuscitation can reverse LPS-induced renal injury in aged mice (34), we added volume resuscitation and antibiotic treatment to the standard CLP model. Animals became clinically ill at 5-6 hours after surgery, at which time they had evidence of liver damage; kidney damage was evident by MRI early (62), but serum creatinine and BUN levels did not significantly increase until 12 hours after surgery (63). With these additions, consistent histological renal damage with significant increase in serum creatinine were observed, not because fluids and antibiotics were harmful to the kidney, but because the animals could survive long enough to develop AKI (34,64).…”

Section: Stent Peritonitis [Casp]); and (C) Infusion Or Instillation mentioning

confidence: 99%

Animal models of sepsis and sepsis-induced kidney injury

Doi

Leelahavanichkul²,

Yuen³

et al. 2009

J. Clin. Invest.

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491

424

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Sepsis and sepsis-induced acute kidney injury: a life-threatening conditionSepsis is a characteristic set of systemic reactions to overwhelming infection. Sepsis, severe sepsis, and septic shock are defined according to established criteria (Table 1) (1). Discovery of antibiotics has dramatically improved the morbidity and mortality of the infectious diseases for the last decades; indeed, antibiotics and volume resuscitation are the first line of sepsis treatment strategy (2). However, overwhelming inflammatory response accompanied by depression in immunological function causes multiple organ injury and determines clinical outcomes. In addition to inflammation and immunological dysregulation, a number of different mechanisms contribute to sepsis at different phases (Figure 1). For instance, systemic hemodynamics evolves from an early hyperdynamic ("warm shock") state to a late hypodynamic ("cold shock") state.Sepsis is the leading cause of death in critically ill patients, and the incidence of sepsis is increasing (3, 4). The mortality rate of severe sepsis is very high (up to 70%), and the calculated costs exceed $15 billion per year in the United States (3). The rate of severe sepsis during hospitalization almost doubled during the last decade and is considerably greater than previously predicted (5). Sepsis causes multiorgan failure, including acute kidney injury (AKI) (6), and patients with both sepsis and AKI have an especially high mortality rate (7). AKI is diagnosed by a sudden decrease in glomerular filtration rate (GFR), the primary measure of kidney function, which is currently detected clinically as a rise in serum creatinine. A multinational prospective observational study including 29,269 critically ill patients revealed that the occurrence of AKI in the intensive care unit (ICU) was approximately 6%, the most frequent contributing factor to AKI being sepsis (50%) (8). Other reports showed that between 45% and 70% of all AKI is associated with sepsis (9-11). Several different pathophysiological mechanisms have been proposed for sepsis-induced AKI: vasodilation-induced glomerular hypoperfusion, dysregulated circulation within the peritubular capillary network, inflammatory reactions by systemic cytokine storm or local cytokine production (12), and tubular dysfunction induced by oxidative stress (13).Continuing concern over the efficacy and safety of the only FDAapproved therapy for severe sepsis (activated protein C) highlights the critical need to improve our understanding of the pathophysiology of sepsis and sepsis-induced AKI and to develop novel treatment strategies for critically ill patients (14). A multitude of potential drug targets have been identified in animal models of sepsis; however, translation from animals to humans has been exceedingly difficult. Several reviews have pointed out that the failure to translate results from animals to humans has been attributed to disease characteristics of sepsis (complexity and heterogeneity), inappropriate clinical trials (study of ineffective drugs...

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Section: Stent Peritonitis [Casp]); and (C) Infusion Or Instillation mentioning

confidence: 99%

Animal models of sepsis and sepsis-induced kidney injury

Doi

Leelahavanichkul²,

Yuen³

et al. 2009

J. Clin. Invest.

Self Cite

491

424

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“…This may be another indication that different pathways mediate injury in the liver as compared with the kidney (6) or may represent a type 2 statistical error secondary to the insensitivity of transminase enzymes at detecting liver dysfunction. However, using mice lacking the protein MyD88 we previously demonstrated that the degree of liver injury (as measured by AST and ALT) does not correspond with sepsis mortality but renal injury closely predicted survival (6,10). Therefore, we believe it is an important finding that anti-CD147 prevented ARF even in the absence of a significant effect on liver injury.…”

Section: Discussionmentioning

confidence: 91%

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Dear

Leelahavanichkul

Aponte

et al. 2007

Critical Care Medicine

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Objective-Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and, therefore, identify new drug targets. Design-Proteomic discovery study and drug target validation Setting-Research institute laboratorySubjects-Three month old C57BL/6 mice Interventions-We used a mouse model of sepsis based on cecal ligation and puncture (CLP) but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in-gel electrophoresis (DIGE). We compared liver proteins from 6 hr post-CLP to shamoperated mice ('early proteins') and 24 hr post-CLP with 6 hr post-CLP ('late proteins'). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction.Results-The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase proteins, coagulation, ER stress, oxidative stress, apoptosis, mitochondrial proteins and nitric oxide metabolism. We found that cyclophilin increased in abundance after CLP. When the receptor for this protein, CD147, was inhibited sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited.Conclusion-By applying proteomics to a clinically relevant mouse model of sepsis we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets.

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“…Twenty contiguous coronal T2-weighted fast-spin echo images (echo train length 4) of 0.5-mm slice thickness were collected with the following parameters: repetition time (TR) ϳ2,500 ms depending on respiration rate; effective echo time ϭ 36 ms; field of view ϭ 20 mm ϫ 20 mm; matrix ϭ 256 ϫ 256; 6 signal averages; total scan time was ϳ16 min. Gadolinium-based G4 dendrimer intravenous contrast was used as described (15). Briefly, a single coronal slice (1-mm thick) through the center of both kidneys was acquired using a Fast Low Angle Shot (FLASH) pulse sequence with the following parameters: repetition time 40 ms, echo time 3.16 ms, Flip angle 30°, field of view 40 ϫ 40 mm, matrix 256 ϫ 256, 4 signal averages.…”

Section: Response To Bumetanide Hsd11b2mentioning

confidence: 99%

A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice

Evans

Livingstone

Kenyon

et al. 2012

American Journal of Physiology-Renal Physiology

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In aldosterone target tissues, 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2 Ϫ/Ϫ mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2 Ϫ/Ϫ mice and controls. Hsd11b2Ϫ/Ϫ mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (ϳ2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2 Ϫ/Ϫ mice (Ͼ6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2 Ϫ/Ϫ mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2 Ϫ/Ϫ mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin. polyuria; polydipsia; aldosterone; corticosterone; aquaporin-2; prenatal programming IN VITRO, ALDOSTERONE AND cortisol have equal affinities for mineralocorticoid receptors (MR) (3). In vivo, however, MR is selectively activated by aldosterone in target tissues such as the distal nephron (aldosterone-sensitive distal nephron; ASDN). This selectivity results from prereceptor metabolism of competing cortisol (corticosterone in rodents), which is an MR ligand, to cortisone (11-dehydrocorticosterone), which is not (16,21).In humans, congenital loss of 11␤ hydroxysteroid dehydrogenase type 2 (11␤HSD2) causes apparent mineralocorticoid excess (AME; OMIM 218030), presenting with hypertension, hypokalemic alkalosis, and a suppressed renin-angiotensinaldosterone system (38, 47). AME reflects activation of MR by glucocorticoids (47): with mineralocorticoid target proteins no longer subject to the homeostatic influence of the renin-angiotensin-aldosterone system, hypertension and electrolyte abnormalities develop secondary to renal salt and water retention. A similar profile is observed when AME is acquired following pharmacological inhibition of 11␤HSD2 (18). In rats, inhibition of 11␤HSD2 stimulates sodium reabsorption in the collecting duct following activation of the epithelial sodium channel (ENaC) (7).To better define the role of 11␤HSD2 in sodium a...

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Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice

Abstract: Dendrimer-enhanced MRI is a novel biomarker that provides information for the early diagnosis, drug responsiveness, and prognosis of sepsis-induced ARF.

Cited by 55 publications

References 26 publications

Animal models of sepsis and sepsis-induced kidney injury

Animal models of sepsis and sepsis-induced kidney injury

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice

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