Hsp72 is an early and sensitive biomarker to detect acute kidney injury.

Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
EMBO Molecular Medicine (Impact Factor: 7.8). 01/2011; 3(1):5-20. DOI:10.1002/emmm.201000105
Source: PubMed

ABSTRACT 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.

0 0
  • [show abstract] [hide abstract]
    ABSTRACT: We previously reported that radicicol (Hsp90 inhibitor) induced a reduction in the renal blood flow and glomerular filtration rate, in part due to a reduction in urinary NO2/NO3 excretion, suggesting that Hsp90 regulates renal vascular tone in physiological conditions. However, there is a lack of information concerning Hsp90α or Hsp90β role on eNOS activity and their association with acute kidney injury (AKI) characterized by an inadequate NO production. This study evaluated the effects of Hsp90α or Hsp90β intra-renal transfection under ischemia/reperfusion (IR) injury. Uninephrectomized (Nx) rats were intra-renally transfected through injections with Hsp90α or Hsp90β cloned into pcDNA3.1(+) or empty vector (EV) at 48 h before inducing IR, as indicated in the following groups: (i) Nx + sham, (ii) Nx + IR, (iii) Nx + IR + EV, (iv) Nx + IR + Hsp90α and (v) Nx + IR + Hsp90β. After 24 h, physiological, histopathological, biochemical and molecular studies were performed. IR-induced renal dysfunction, structural injury, tubular proliferation, the elevation of urinary Hsp72 and the reduction of urinary NO2/NO3 excretion. These alterations were associated with reduced eNOS-Hsp90 coupling and changes in the eNOS phosphorylation state mediated through a reduction in PKCα and increased Rho kinase expression. In contrast, intra-renal transfection of Hsp90α or Hsp90β prevented IR injury that was associated with the restoration of eNOS-Hsp90 coupling, eNOS activating phosphorylation and PKCα and Rho kinase levels. Here we showed that eNOS-Hsp90 uncoupling plays a critical role in promoting NO reduction during IR. This effect was effectively reversed through Hsp90α or Hsp90β intra-renal transfection, suggesting their implication in regulating NO/eNOS pathway and the renal vascular tone.
    Nephrology Dialysis Transplantation 10/2013; · 3.37 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Fluoride is usually found in groundwater at a very wide range of concentration between 0.5 to 25ppm. At present, few studies have assessed the renal effects of fluoride at environmentally relevant concentrations. Furthermore, most of these studies have used insensitive and nonspecific biomarkers of kidney injury. The aim of this study was to use early and sensitive biomarkers to evaluate kidney injury after fluoride exposure to environmentally relevant concentrations. Recently weaned male Wistar rats were exposed to low (15ppm) and high (50ppm) fluoride concentrations in drinking water for a period of 40days. At the end of the exposure period, kidney injury biomarkers were measured in urine and renal mRNA expression levels were assessed by real time RT-PCR. Our results showed that the urinary kidney injury molecule (Kim-1), clusterin (Clu), osteopontin (OPN) and heat shock protein 72 excretion rate was significantly increased in the group exposed to the high fluoride concentration. Accordingly, fluoride exposure increased renal Kim-1, Clu and OPN mRNA expression levels. Moreover, there was a significant dose-dependent increase in urinary β-2-microglobulin and cystatin-C excretion rate. Additionally, a tendency towards a dose dependent increase of tubular damage in the histopathological light microscopy findings, confirmed the preferential impact of fluoride on the tubular structure. All of these changes occurred at early stages in which, the renal function was not altered. In conclusion using early and sensitive biomarkers of kidney injury, we were able to found proximal tubular alterations in rats sub-chronically exposed to fluoride.
    Toxicology and Applied Pharmacology 08/2013; · 3.98 Impact Factor
  • Source
    [show abstract] [hide abstract]
    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; · 3.19 Impact Factor

Full-text (2 Sources)

Available from
Nov 19, 2013