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Annals of Clinical & Laboratory Science 38:57-64 (2008)
© 2008 Association of Clinical Scientists

Heat Shock Protein Expression Is Highly Sensitive to Ischemia-Reperfusion Injury in Rat Kidneys

Ping L. Zhang1,2, Mingyue Lun2, Charles M. Schworer2, Thomas M. Blasick2, Kathryn K. Masker2, Jay B. Jones1 and David J. Carey2
1 Division of Laboratory Medicine, Geisinger Medical Center, and 2 Weis Center for Research, Geisinger Clinic. Danville, Pennsylvania

Address correspondence to Ping L. Zhang, M.D., Ph.D., at his present address: Department of Anatomic Pathology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 48073-6769, USA; tel 248 898 9070; fax 248 898 9054; e-mail pinglzhang{at}gmail.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Renal injury is known to trigger upregulation of many intracellular signal proteins, but those most sensitive in responding to renal injury remain debatable. We used gene microarray analysis to compare gene expression in rat kidneys subjected to early ischemia-reperfusion injury (30 min of renal ischemia and 3 hr of reperfusion) with non-ischemic kidneys as controls. Among 31,100 genes analyzed, microarray analysis revealed 21 genes with >3-fold increase in expression in ischemic kidneys compared to control non-ischemic kidneys. These upregulated genes included heat shock protein 70 (43-fold), heat shock protein 27 (12-fold), heme oxygenase-1 (10-fold), kidney injury molecule-1 (8-fold), and several subtypes of S100 calcium-binding proteins (3.1- to 7.5-fold). Following a prolonged reperfusion period (48 hr) after 30 min of ischemia, acute tubular necrosis was obvious in the S3 segment of proximal tubules of ischemic kidneys. Injured proximal tubules showed upregulated expression of heat shock protein 70 by immunohistochemistry and by Western blotting. These data suggest that heat shock proteins (eg, heat shock protein 70, heat shock protein 27, and heme oxygenase-1) are crucial for renal cell response to ischemic injury and that heat shock protein 70 is a highly sensitive intracellular marker of ischemia-reperfusion injury.

Keywords: acute tubular necrosis, heat shock proteins, kidney injury molecule-1, renal ischemia


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Acute tubular necrosis (ATN) has a high prevalence in patients with renal diseases and can be diagnosed in approximately 1% of hospitalized patients [1]. Proximal tubules are the target structures for identifying ATN in human renal disease. However, morphologic changes in proximal tubules during ATN vary from minimal to severe, including diminished brush borders, dilated tubules, and sloughed epithelial cells in the tubular lumina. For this reason, molecular markers to identify or confirm renal tubular injury are greatly needed.

Based on animal models, the S3 segment is the region of renal tubules that is most vulnerable to ischemic and toxic injury, because this segment is physically located in the medulla, a zone of low oxygen tension compared to the highly oxygenated cortex, and cells in the S3 segment rely extensively on ATP for active reabsorption of ions. Since the S3 segment of rat kidney is thick in the outer strip of the outer medulla [2], rats are used widely to study the vulnerability of renal tubules to ischemia-reperfusion injury and chemical nephrotoxicity.

During the early phase of renal injury many genes show altered expression, including transcription factors (eg, hypoxia inducible transcription factor, egr-1, and c-fos), stress proteins (eg, heat shock protein 70 [HSP70]), and growth factors (eg, fibroblast growth factor) [3–6]. Several previous studies investigated the global alterations of gene expression in ischemic rat kidneys using gene microarray techniques [7–9]. Yoshida et al [7] reported upregulation of heme oxygenase-1 expression (among 2100 genes probed) in rat kidneys after 30 min of ischemia followed by 1–4 days of reperfusion. Supavekin et al [8] found platelet growth factor and epidermal growth factor (among 8979 genes probed) upregulated in kidneys after 45 min of ischemia and 3–24 hr of reperfusion. Mishra et al [9] characterized the upregulation of gelatinase-associated lipocalin (NGAL) in early post-ischemic mouse kidney and noted its presence in the urine.

The current study examined gene expression in the early stages of ischemia-reperfusion injury in rat kidneys using microarrays with probes for 31,000 genes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Animals.  Adult male Sprague-Dawley rats (250 to 280 g, bw) were purchased from Charles River Breeding Laboratories (Boston, MA). The rats were divided into 3 groups (7 in each group). For surgical procedures the rats were anesthetized by ip pentobarbital (50 mg/100 g, bw) and kept on a warming pad. Rats in Group 1 received right nephrectomy (contralateral control) and the left kidney was untouched (sham control) but was harvested 3 hr after the right nephrectomy. Rats in Group 2 received right nephrectomy (contralateral control) and the left renal artery was clamped for 30 min, followed by 3 hr of reperfusion, after which time the left kidney was harvested. Rats in Group 3 underwent right nephrectomy (contralateral control); the left renal artery was ligated for 30 min followed by 2 days of reperfusion, after which time the left kidney was harvested. Aortic blood was collected from all rats at the time of left kidney removal and serum creatinine concentration was measured colorimetrically.

RNA extraction and gene microarray analysis.  Total RNA was isolated from contralateral control kidneys (n = 6), from sham-control kidneys (n = 3), and from kidneys with ischemia and 3 hr of reperfusion (n = 3) using TRIzol reagent (Invitrogen Corp., Carlsbad, CA). The RNA was used as template for synthesis of double-stranded cDNA by reverse transcription. Complementary RNA was synthesized and labeled with biotin by in vitro transcription (Enzo Biochem, New York, NY). Fifteen µg of labeled cRNA from each sample was hybridized to Rat Genome 230 2.0 GeneChip (Affymetrix) using the manufacturer’s procedures for prehybridization, hybridization, and washing. After hybridization the chips were stained with streptavidin-phycoerythrin. Antibody amplification was accomplished with a biotin-linked antibody to streptavidin (Vector Laboratories, Burlingame, CA) and a goat-IgG blocking antibody (Sigma, St Louis, MO). A second application of the streptavidin-phycoerythrin dye was used after additional wash steps were completed. After automated staining and wash protocols (Affymetrix protocol EukGE-2v4), the assays were scanned by the Affymetrix GeneChip scanner (Agilent, Palo Alto, CA) and quantitated with Microarray suite version 5.0 (Affymetrix). Rat Genome 230 2.0 GeneChips contain probes for about 31,100 gene products. Median intensity was used for normalization of the arrays.

Immunohistochemical staining for HSP70.  Tissue blocks were routinely formalin-fixed and paraffin-embedded. For each block, one 5-µm section was de-waxed in Histoclear (xylene substitute) and rehydrated with graded ethanols to water. A set of sections underwent routine hematoxylineosin staining. Slides underwent antigen retrieval with Target Retrieval Solution (DAKO) for 20 min at 95°C and then were cooled at room temperature for 20 min. Slides were rinsed with water and placed in 0.5 M Tris-HCl, 0.05% Tween-20 for 5 min. Subsequently, a DAKO Autostainer (Model E172566) was used to incubate the slides with rabbit anti-human HSP70 antibody (Santa Cruz Biotechnology, Santa Cruz, CA, 1:50 dilution), peroxidase-conjugated secondary goat anti-rabbit antibody (DAKO, pre-diluted), and 3,3'-diaminobenzidine chromogen solution. Slides were rinsed with water, counterstained, and coverslipped for light microscopy. HSP70 staining of tubular epithelial cells was scored using a graded scale from 0 to 3 (0, no staining; 0.5, minimal fine granular staining; 1, weak granular staining; 2, moderate fine granular staining; and 3, strong large granular staining).

Western blot analysis.  Renal cortex tissue was cut into tiny pieces and lysed in lysis buffer. Tissue homogenates from each sample were electrophoresed on 10% SDS-PAGE. The fractionated proteins were transferred to polyvinylidene fluoride membrane, which were incubated with HSP70 antibody (1:1000 dilution) followed by secondary antibody conjugated with horseradish peroxidase. Immunoreactive proteins were visualized by enhanced chemiluminescence (Amersham Pharmacia Biotech, Piscataway, NJ). Staining with anti-β-actin antibody (Sigma) (1:4,000 dilution) was used to evaluate the evenness of the protein loading.

Statistics.  Results were expressed as mean ± SE. ANOVA was used to compare data between groups, followed by Fisher’s exact test. A p =0.05 was considered significant. Affymetrix GeneChip Operating Software v 2.1 was used to make standard adjustments for artifacts, noise, and background and to calculate a detection p value for each gene on each array. These data were imported into a spreadsheet where they were sorted by the detection call. All gene probes that were scored as present or marginal on two or more of the arrays in one of the groups were selected for further analysis. These data were imported into Spotfire Decision Site v 8.1 and the data set was normalized by first scaling each experiment by the mean, followed by z score calculation of the gene probes. The resulting data were analyzed using one-way ANOVA to determine which genes were significantly changed. The Spotfire software was used to cluster the experiment (columns) and gene probes (rows) into a heat map by using the unweighted average and Euclidean distance methods.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
Serum creatinine.  Rats with 30 min of renal ischemia and 3 hr of reperfusion had serum creatinine levels that were twice those of control rats (Table 1Go). Creatinine levels remained high following 48 hr of reperfusion post-ischemic insult. These results show that the experimental protocol effectively produced ischemia-reperfusion injury in rat kidneys.


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  		Table 1. Serum creatinine in control rats and rats with renal ischemia.
 
Gene microarray analysis.  Effects of ischemia-reperfusion injury on renal gene expression were investigated by gene microarray analysis. Fig. 1Go is a heat map that shows statistically significant changes in gene expression between kidneys subjected to 30 min of ischemia and 3 hr of reperfusion compared to the sham and contralateral controls. Among the 31,100 genes interrogated, a total of 456 genes showed significant changes. Of these, a total of 198 genes were upregulated in ischemic kidneys.


Figure 1
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  		Fig. 1. Hierarchal clustering of microarray expression data. Gene microarray analysis of rat kidneys with ischemia/reperfusion injury (L1–L3) was compared to non-ischemic kidneys of control rats (L4–L6) and contralateral non-ischemic kidneys (R1–R6). The vertical columns represent individual samples. The horizontal rows represent the individual gene products. The colors in each cell indicate the expression level of a particular gene in a sample relative to the mean level from all 12 samples for that gene. The color scale extends from bright red (maximum upregulation) to bright green (maximum downregulation).

 
To identify genes with the largest degree of upregulation, the ratio of expression signal in ischemic compared to control kidneys was calculated. Twenty-one genes were upregulated >3-fold in ischemic kidneys compared to contralateral control kidneys (Table 2Go). The highly upregulated genes included several members of the heat shock family of proteins (eg, HSP70, heat shock protein 27 [HSP27], heme oxygenase-1), kidney injury molecule-1 (KIM-1), and S100 calcium-binding proteins.


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  		Table 2. Genes upregulated more than 3-fold after renal ischemic insult in rats.
 
HSP70 expression.  The gene with greatest increase in expression in response to ischemia-reperfusion was HSP70. Experiments were performed to investigate the utility of HSP70 as a marker of renal ischemia-reperfusion injury. Histological analysis of hematoxylineosin stained sections revealed that kidneys subjected to 30 min of ischemia and 3 hr of reperfusion were no different from the contralateral control kidneys that showed unremarkable S3 segments of the proximal tubules and distal nephron tubules (Fig. 2AGo). However, after 48 hr of reperfusion following 30 min of ischemia, acute tubular necrosis, characterized by sloughed epithelial cells in the lumen and occasional mitosis, was evident in the S3 segment of proximal tubules (Fig. 2BGo). Under normal conditions, kidneys displayed HSP70 expression mainly in distal nephron tubules, but minimally in proximal tubules (Fig. 2CGo). This expression pattern and intensity of HSP70 protein was not altered by 30 min of ischemia followed by 3 hr of reperfusion. However, ischemia followed by prolonged (48 hr) reperfusion clearly resulted in overexpression of HSP70 protein in the S3 segments of proximal tubules (Fig. 2DGo). After 48 hr reperfusion, HSP70 staining intensity in S3 segments of proximal tubules from injured kidneys (0.87 ± 0.09 arbitrary units) was significantly higher than the scores for contralateral controls (0.21 ± 0.10 arbitrary units). Distal nephron tubules appeared to show slightly upregulated expression of HSP70 following the ischemia-reperfusion injury. However, because the baseline level of HSP70 expression was high in control kidneys, the difference of HSP70 intensity between distal nephron tubules of injured kidneys and control kidneys was difficult to quantitate.


Figure 2
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  		Fig. 2. Histological and immunohistochemical analysis of S3 segment of proximal tubules from control and ischemia-reperfusion injured kidneys. A. Normal-appearing outer strip of medulla including S3 segment of proximal tubules (S3) and distal nephron tubules (DT) from the contralateral (right) control kidney of (hematoxylineosin stain). B. Acute tubular necrosis in S3 segment of proximal tubules from a kidney following 30 min of renal ischemia and 48 hr of reperfusion (hematoxylineosin stain). C. In the contralateral control kidney, HSP70 was positively present in distal nephron tubules but was minimally expressed in S3 segment of proximal tubules. D. After ischemia and 48 hr of reperfusion injury S3 segment of proximal tubules showed overexpression of HSP70 in cytoplasm of intact epithelial cells and sloughed epithelial cells in the lumen. (x 600 for A–D.)

 
Increased expression of HSP70 was confirmed by Western blot analysis (Fig. 3Go). Kidneys subjected to 30 min of ischemia and 48 hr of reperfusion had a 4.8-fold increase in HSP70 expression compared to contralateral control kidneys (224,449 ± 20,059 arbitrary units in injured kidneys vs 46,987 ± 7625 units in control kidneys).


Figure 3
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  		Fig. 3. Western blot analysis of HSP70 in control and ischemic-reperfusion kidneys. Lanes 1–3: low expression of HSP70 protein from the cortex of 3 contralateral (right) control kidneys. Lanes 4–6: Upregulated expression of HSP70 proteins from the cortex of respective left kidneys following ischemia and 48 hr of reperfusion injury. There was no difference in the level of actin between control and injured kidneys, indicating even loading of proteins.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
The morphologic changes associated with ATN can be a spectrum ranging from minimal alterations to tubular necrosis with frank renal infarction [9,10]. In the earlier or acute phase of renal insult, impaired renal function is associated with only limited histologic changes. The paradox of limited histologic alteration in the face of whole organ failure has been recognized for more than 40 years [11]. Our current findings support this view. Renal ischemia followed by 3 hr of reperfusion resulted in elevated serum creatinine levels similar to those with the same period of renal ischemia followed by 48 hr of reperfusion. No morphologic alteration was noted after 3 hr of reperfusion, whereas S3 segments showed obvious ATN after 48 hr of reperfusion. The loss of renal tubule function was similar, despite the differences in morphology.

Alterations in the expression of many genes have been observed during the early stages of response to renal injury [3–6]. Altered genes include transcription factors (such as hypoxia inducible transcription factor, egr-1, and c-fos), stress proteins (such as HSP70), and growth factors (such as fibroblast growth factor). Previous gene microarray studies showed that heme oxygenase-1 (among 2100 genes probed) [7], certain growth factors (among 8979 genes probed) [8], and NGAL (8979 genes probed) [9] are sensitive molecular signals of renal injury in animal models.

In the present study we analyzed the expression of more than 30,000 genes in rat kidneys following a short period of reperfusion after ischemia. These experiments identified a set of highly upregulated genes that included several stress proteins (HSP70, HSP27, and heme oxygenase-1). Our study also showed that KIM-1 is markedly upregulated during the early phase of response to ischemia-reperfusion injury. KIM-1 belongs to an adhesion molecule family and is predominantly expressed in the kidney [12]. Its expression is associated with epithelial injury of proximal tubules in humans and rats [12–14]. During severe ischemic or toxic injury, KIM-1 is upregulated along the internal luminal surface of proximal tubules, but not in other types of tubules (such as Henle’s loop or distal tubules) [13,14]. In addition, KIM-1 protein levels are elevated in urine from patients with kidney injury compared to controls [13]. The biological function of KIM-1 is unknown and its role in renal ischemia-reperfusion injury is a mystery.

HSP70 is a molecular chaperone that is involved in protein folding and maturation [15]. Since it has the functions of preventing protein aggregation and refolding of denatured proteins, pre-conditionally upregulating HSP70 has been found to be cytoprotective in the kidney and heart [16–18]. Similarly, the other two heat shock proteins that were upregulated in the present study, HSP27 and heme oxygenase-1, are also considered to play critical roles in pre-conditional cytoprotection in injured kidneys [19,20]. Therefore, it is likely that the upregulation of heat shock proteins that was observed in our study reflects a physiological response that protects injured kidneys from cellular damage.

It is generally believed that non-proximal tubules are less vulnerable than S3 segments because non-proximal tubules may not be involved in active transport despite their location in hypoxic zones [21,22].

We found that non-proximal tubules possess high levels of HSP70 regardless of their location in the cortex or the medulla. It seems likely that normally high levels of heat shock proteins are cytoprotective in non-proximal tubules when the kidney is subject to ischemic or toxic injury.

In conclusion, we found that when the kidney was subjected to ischemia-reperfusion injury, heat shock proteins were among the gene products that responded to the highest degree from more than 30,000 genes analyzed. This early response to renal injury supports the notion that heat shock proteins represent an important group of cytoprotective proteins intrinsically existing in these cells. Furthermore, HSP70 provides a sensitive molecular marker for renal ischemia-reperfusion injury.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported in part by grants from the Geisinger Clinical Research Fund and the Pennsylvania Department of Health CURE Program. The authors appreciate excellent secretarial support from Ms. Elisa A. Steinbacher.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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