Hsp72 is an early and sensitive biomarker to detect acute kidney injury: Hsp72 as a novel biomarker to detect AKI

Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
EMBO Molecular Medicine (Impact Factor: 8.67). 01/2011; 3(1):5-20. DOI: 10.1002/emmm.201000105
Source: PubMed


This study was designed to assess whether heat shock protein Hsp72 is an early and sensitive biomarker of acute kidney injury (AKI) as well as to monitor a renoprotective strategy. Seventy-two Wistar rats were divided into six groups: sham-operated and rats subjected to 10, 20, 30, 45 and 60 min of bilateral ischemia (I) and 24 h of reperfusion (R). Different times of reperfusion (3, 6, 9, 12, 18, 24, 48, 72, 96 and 120 h) were also evaluated in 30 other rats subjected to 30 min of ischemia. Hsp72 messenger RNA (mRNA) and protein levels were determined in both kidney and urine. Hsp72-specificity as a biomarker to assess the success of a renoprotective intervention was evaluated in rats treated with different doses of spironolactone before I/R. Renal Hsp72 mRNA and protein, as well as urinary Hsp72 levels, gradually increased relative to the extent of renal injury induced by different periods of ischemia quantified by histomorphometry as a benchmark of kidney damage. Urinary Hsp72 increased significantly after 3 h and continued rising until 18 h, followed by restoration after 120 h of reperfusion in accord with histopathological findings. Spironolactone renoprotection was associated with normalization of urinary Hsp72 levels. Accordingly, urinary Hsp72 was significantly increased in patients with clinical AKI before serum creatinine elevation. Our results show that urinary Hsp72 is a useful biomarker for early detection and stratification of AKI. In addition, urinary Hsp72 levels are sensitive enough to monitor therapeutic interventions and the degree of tubular recovery following an I/R insult.

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    • "Supporting this finding, we previously found in critically ill patients with two or more organ failure that urinary Hsp72 level only increased in the patients diagnosed with AKI (Barrera-Chimal et al., 2011). Moreover, we recently showed that Hsp72 was enough sensitive and specific to predict AKI in critically ill patients up to 3 d before the diagnosis. "
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    ABSTRACT: We demonstrated that urinary heat shock protein of 72 KDa (Hsp72) is a sensitive biomarker for the early detection of acute kidney injury (AKI). However, whether Hsp72 induction during an AKI episode is kidney-specific is unknown, as well as, the degree of Hsp72 stability in urine samples. In rats that underwent bilateral renal ischemia and reperfusion (I/R), Hsp72 levels were evaluated in several tissues and in collected urines under different storage and temperature conditions, as well as in variable numbers of freeze-thaw cycles. The effect of room temperature and five freeze-thaw cycles on urinary Hsp72 levels was also evaluated in urine samples from AKI patients. We found that Hsp72 increased exclusively in the renal cortex of I/R group, emphasizing its performance as an AKI biomarker. Urinary-Hsp72 remained constant at room temperature (48 h), during 9 months of storage and was not affected by five freeze/thaw cycles.
    Biomarkers 10/2015; DOI:10.3109/1354750X.2015.1096305 · 2.26 Impact Factor
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    • "Most strikingly, in our experiments protection by BIRB796 was afforded under severe ischemic conditions (ischemia time of 1 hour), as documented by the established functional markers creatinine and urea. While serum creatinine and urea provide measures of kidney function, increase in Hsp70 [29] and in particular NGAL [51,52] are indicators of renal epithelial injury [53]. These findings are also corroborated by the observed protective effect of p38MAPK inhibition on the survival of tubular epithelial cells (Figure  5B, C). "
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    ABSTRACT: Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects. Here we identified p38MAPKalpha as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKalpha signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death. These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.
    Cell Communication and Signaling 01/2014; 12(1):6. DOI:10.1186/1478-811X-12-6 · 3.38 Impact Factor
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    • "GG genotype has been linked to elevated Hsp70 circulating levels or gene expression in chronic heart failure (Gombos et al. 2008) and in diabetes-atherosclerotic patients (Giacconi et al. 2005), suggesting an increased vascular damage in GG carriers (Ogawa et al. 2008). Hsp70 is also considered a sensitive biomarker of renal injury and it is overexpressed in diabetic nephropathy (Barrera-Chimal et al. 2011; Calabrese et al. 2007). Some evidence shows an association of GG genotype with an increased risk to develop renal complications in diabetes with a faster progression to the end-stage of renal failure (Buraczynska et al. 2009). "
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    ABSTRACT: Proinflammatory cytokines and heat shock proteins play relevant roles in the pathogenesis of inflammatory diseases. We investigated whether Hsp70 1267 A/G and TNF-α -308 G/A polymorphisms are associated with proinflammatory mediators, zinc status and laboratory parameters in 1,078 healthy elderly from ZincAge study. Hsp70 1267 A/G genotype and allele distribution were similar among various European countries, while a TNF-α genetic heterogeneity was observed between the Northern and the Southern European populations, with a major frequency of the -308 A variant in France, Germany and Poland. We used linear regression models to test additive, dominant or recessive associations of each SNP with proinflammatory mediators, laboratory parameters, metallothioneins and zinc status. Hsp70 1267 A/G SNP, but not TNF-α -308 G/A SNP, influences TNF-α and IL-6 plasma levels under additive, dominant and recessive models (for TNF-α only). An association between Hsp70 1267 A/G SNP and zinc plasma levels was observed in the dominant model. In particular, G allele carriers showed increased circulating pro-inflammatory cytokines and zinc. Moreover, both these SNPs affect creatinine levels suggesting a possible influence on renal function. In conclusion, Hsp70 1267 A/G SNP is associated with pro-inflammatory cytokine production in healthy elderly and might represent a possible determinant of individual susceptibility to inflammatory diseases.
    Biogerontology 11/2013; 15(1). DOI:10.1007/s10522-013-9480-1 · 3.29 Impact Factor
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