Nephrology Dialysis Transplantation

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Nephrol Dial Transplant (2000) 15: 529-535
© 2000 European Renal Association-European Dialysis and Transplant Association

Interstitial expression of heat shock protein 47 and -smooth muscle actin in renal allograft failure

Katsushige Abe, Yoshiyuki Ozono, Masanobu Miyazaki, Takehiko Koji¹, Kei Shioshita, Akira Furusu, Shoko Tsukasaki, Fukuzo Matsuya², Nobuko Hosokawa³, Takashi Harada⁴, Takashi Taguchi⁵, Kazuhiro Nagata³ and Shigeru Kohno

Second Department of Internal Medicine, ¹ Department of Histology and Cell Biology, ² Department of Urology, ⁴ Division of Renal Care Unit and ⁵ Second Department of Pathology, Nagasaki University School of Medicine, Sakamoto, Nagasaki and ³ Department of Cell Biology, Chest Disease Research Institute, Kyoto University, Kyoto, Japan

Correspondence and offprint requests to: Masanobu Miyazaki, MD, Second Department of Internal Medicine, Nagasaki University School of Medicine, 1–7-1 Sakamoto, Nagasaki 852–8501, Japan.

	Abstract

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Background. Tubulointerstitial inflammation and fibrosis are the main pathological features of chronic renal allograft rejection, which is characterized by accumulation of extracellular matrix protein. Heat shock protein 47 (HSP47), known as a collagen-specific stress protein, is thought to be a molecular chaperone during the processing and/or secretion of procollagen. HSP47 is thought to be involved in the progression of fibrosis, but its expression in chronic renal allograft rejection is still unknown.

Methods. We examined the expression of HSP47 together with that of -smooth muscle actin (-SMA), a marker of myofibroblasts, and CD68, a marker of macrophages, by immunohistochemistry in allograft kidney tissues. Uninvolved portions of surgically removed kidneys with tumours served as control tissue.

Results. Expression of HSP47 was detected in the interstitium of fibrotic regions of allograft kidneys. Cells positive for HSP47 were also stained for -SMA and type I collagen, and the expression of HSP47 correlated with the degree of interstitial fibrosis. Furthermore, the expression of HSP47 correlated with the number of infiltrating macrophages. In contrast, HSP47 and -SMA were not expressed in the control tissues, sections of 1 h post-transplantation biopsy specimens and acute allograft rejection without fibrosis.

Conclusion. Our results suggest that HSP47 may contribute to the progression of interstitial fibrosis in allograft renal tissues.

Keywords: HSP47; myofibroblasts; transplantation kidney; fibrosis

	Introduction

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The mean graft survival time after renal allotransplantation has improved in recent years [1,2], although graft loss due to irreversible chronic rejection is still a major problem and its pathogenesis remains to be established. One of the pathological features of chronic renal allograft rejection is the accumulation of inflammatory cells and progression of interstitial fibrosis, which is preceded by increased production of extracellular matrix proteins [3,4]. However, the pathogenesis of fibrogenesis in chronic rejection is not yet fully understood.

A 47 kDa heat shock protein HSP47, first described as a collagen-binding stress protein, acts like a molecular chaperone during processing and/or secretion of procollagen [5]. Several studies have shown that the expression of HSP47 is closely related to collagen synthesis. For example, Nagata et al. [6] demonstrated that the synthesis of HSP47 paralleled that of types I and IV [7] collagen. Masuda et al. [8] showed that HSP47 was induced during the progression of rat liver fibrosis with production of collagen types I and III. In recent studies, the expression of HSP47 was shown to be associated with increased staining of collagen types I, III and IV in an experimental model of interstitial fibrosis of the kidney [9,10]. Furthermore, using antisense oligonucleotides against HSP47 in an experimental model of glomerulonephritis induced by an anti-Thy-1 antibody, Sunamoto and co-workers [11] showed that attenuation of sclerotic lesions and expression of collagen in glomeruli coincided with a reduction of HSP47 expression. These results suggest that HSP47 plays an important role in collagen synthesis in various types of cells.

Several types of renal cells, including mesangial cells, glomerular epithelial cells and tubular epithelial cells, are capable of producing collagen [12]. In chronic tubulointerstitial injury of a variety of renal diseases, myofibroblasts, which can be differentiated from fibroblasts and are considered as activated fibroblasts, are thought to be the main source of interstitial matrix collagen [13]. These myofibroblasts are also known to express a variety of cytoskeletal proteins, particularly -smooth muscle actin (-SMA) [14]. With regard to the expression of -SMA in the kidney, several studies have identified -SMA-positive cells in the fibrotic interstitium in experimental [15] and human glomerulonephritis [16]. In the latter study, the expression of -SMA correlated positively with the degree of tubulointerstitial fibrosis [16]. Based on these findings, it is postulated that -SMA-positive cells may also be involved in tubulointerstitial fibrosis and the progression of chronic rejection of renal allograft tissue.

In the present study, we examined human renal allograft rejection tissues by immunohistochemistry for HSP47 and -SMA. Our results showed that the expression of HSP47 significantly correlates with tubulointerstitial fibrosis and that -SMA-positive myofibroblasts with simultaneous HSP47 expression are the main source of collagen production in tissues of chronic renal rejection. We also demonstrated that infiltrating macrophages are potentially involved in the induction of HSP47 expression in fibroblasts.

	Materials and methods

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Patients
Twenty five renal allograft biopsy specimens were obtained from 23 patients who received their renal allografts at our institution, Nagasaki University Hospital (Table 1). The mean age of these patients was 38 years (range 25–52). In 18 patients, renal biopsy was performed because of rising serum creatinine concentrations or delayed graft function. The other seven biopsy specimens were obtained 1 h after transplantation (1 h post-transplant tissue). No fibrosis was observed in the latter tissues. All patients received immunosuppressive therapy consisting of prednisolone and immunosuppressive agents such as azathioprine and cyclosporin A (CsA). Histological grading of the tissue samples was based on the Banff classification criteria [17]. The tissue samples were considered adequate for diagnostic purposes, and light microscopic, immunofluorescence and electron microscopic examinations were performed to establish the histological diagnosis. The histological classification of the biopsy specimen was established by two pathologists who were blinded to the results of immunohistochemical study. The following criteria were used for the histopathological diagnosis of renal allograft biopsy specimens.

View this table: [in this window] [in a new window]   Table 1. Patients characteristics

 
Acute allograft rejection (three cases).
Acute rejection was diagnosed when interstitial inflammation was documented either alone or in association with intimal or transmural arteritis. Interstitial fibrosis and tubular atrophy were not observed in these sections.

Chronic allograft rejection (10 cases).
The histologic diagnosis was based on the presence of interstitial fibrosis, tubular atrophy and vascular changes such as arterial fibrous initial thickening, and glomerular changes such as glomerular tuft shrinkage, sclerosis and thickening or wrinkling of the basement membrane.

CsA toxicity (five cases).
Features of CsA cytotoxicity including isometric vacuolization of tubules, eosinophilic inclusions, microcalcification, hyaline arteriolar thickening and striped or patch fibrosis were identified by light microscopy.

Normal renal tissues were obtained from macroscopically normal sections of five kidneys with renal cell carcinomas and served as control. The study protocol was approved by the Human Ethics Review Committee of Nagasaki University School of Medicine and a signed consent form was obtained from each subject.

Immunohistochemistry
Immunohistochemistry was performed using paraffin-embedded tissue sections (4 µm thick) using the avidin–biotin complex kit (Vectastain, Elite ABC Kit), with the following primary antibodies: monoclonal antibodies (mAbs) against HSP47 (StressGen), -SMA (Sigma Chemical Co., St. Louis, MO) and CD68 (DAKO M718 Dakopatts, Glostrup, Denmark), which were used as markers for macrophages/monocytes and against human type I collagen (Fuji Chemical Co.). Negative control studies were performed by using irrelevant mouse IgG with the same subclass of the first antibodies, non-specific mouse IgG1 (DAKO X0931) and IgG2 (DAKO X0943) instead of the primary antibodies, showing no positive cells (data not shown).

In order to detect both HSP47 and -SMA simultaneously in the same tissue section, double immunostaining was performed. Following staining of HSP47 as described above, tissue sections were washed with phosphate-buffered saline (PBS) to stop the colour reaction. Sections were then blocked with a blocking solution containing 20% normal swine serum (DAKO X901), 5% fetal calf serum (Gibco-BRL, Gaithersburg, MD) and 5% bovine serum albumin (Sigma) in PBS. In the next step, tissue sections were first incubated overnight with -SMA antibody at 4°C, followed by incubation with horseradish peroxidase (HRP)-conjugated rabbit anti-mouse antibody (DAKO P206) and HRP-conjugated swine anti-rabbit antibody (DAKO P399). A second chromogen, True Blue (Kinkegaard & Perry Laboratories, MD), was applied and sections were incubated, rinsed with distilled water and mounted. Tissue sections were not counterstained with methyl green since the counterstain can interfere with the chromogen colour.

In this study, we examined seven different fields of the cortical interstitium. Under a low magnification (x50), the area of each section was 0.25 mm². In a total of 105 fields, we calculated the percentage of areas positive for HSP47, -SMA and type I collagen using a computer image analyser (Olympus). We also counted the number of CD68-positive cells. In each designated field, interstitial fibrosis was scored semiquantitatively in Masson's trichrome-stained renal biopsies, as previously described [15]: score 0=normal interstitium and tubules; score 1=mild fibrosis with minimal interstitial thickening between the tubules; score 2=moderate fibrosis with moderate interstitial thickening between tubules; score 3=severe fibrosis with severe interstitial thickening between the tubules.

Statistical analysis
Correlation coefficients were tested for statistical significance using the Spearman's rank test and Pearson's rank coefficients. A P-value <0.05 denoted the presence of a statistically significant difference.

	Results

Top Abstract Introduction Materials and methods Results Discussion References

 
Immunohistochemistry
Immunoreactivity for HSP47 (Figure 1A) was not observed in the tubulointerstitium of the normal kidney.

View larger version (147K): [in this window] [in a new window]   Fig. 1. Lack of expression of HSP47 in (A) renal sections of control kidney and (B) 1 h post-transplantation kidney. (C, D) Immunohistochemistry for HSP47 in chronic renal allograft rejection kidney. HSP47 was expressed on tubular epithelial cells (C, arrowheads) and spindle-shaped interstitial cells (D, arrowheads). Magnification: (A) and (B) x100; (C) and (D) x120.

 
HSP47 was not expressed in the tubulointerstitium (Figure 1B) in all tissue samples obtained from 1 h post-transplantation kidneys. In tissue sections of acute allograft rejection, which showed no interstitial fibrosis, immunoreactive HSP47 was not detected in the tubulointerstitium (data not shown). In contrast, tissues of chronic allograft rejection or CsA toxicity showed intense immunoreactivity for HSP47 in the tubulointerstitium (Figure 1C and D). HSP47 was localized in tubular epithelial cells (Figure 1C) and spindle-shaped interstitial cells (Figure 1D).

In order to identify the type of interstitial cells expressing HSP47, we performed immunohistochemistry for -SMA, a marker for activated fibroblasts (myofibroblasts) and CD68, in addition to staining for HSP47 in adjacent sections. The majority of interstitial cells expressing HSP47 (Figure 2A) were also positive for -SMA (Figure 2B). Moreover, double immunostaining for HSP47 and -SMA confirmed the double-positive cells in the same section (Figure 3A and B). Moreover, several cells positive for CD68 were present around HSP47-positive cells in the interstitium (Figure 2A and C). Using the computer image analyser, we compared the percentage of areas positive for HSP47 with that for -SMA and the number of CD68-positive cells in adjacent fields. The expression of HSP47 significantly correlated with that of -SMA and the number of CD68-positive cells (Figure 4A and B).

View larger version (155K): [in this window] [in a new window]   Fig. 2. Immunohistochemistry for HSP47, -SMA, CD68 and type I collagen in chronic renal allograft rejection kidney (magnification x200). (A) Note the expression of HSP47 in the tubulointerstitium (arrows). (B) An adjacent section to that in (A) stained for -SMA. The majority of HSP47-positive cells are also stained for -SMA (arrows). (C) An adjacent section to that in (A) is shown. A number of CD68-positive cells are also present in the interstitial spaces with a distribution similar to that of HSP47. (D) Note the expression of type I collagen in the interstitial area of chronic renal allograft rejection kidney. (E) An adjacent section to that in (D) showing the expression of HSP47 in the interstitium. The majority of interstitial cells express both type I collagen and HSP47. (F) An adjacent section to that in (D). Staining for -SMA showing a distribution similar to that of type I collagen in the interstitium.

 

View larger version (74K): [in this window] [in a new window]   Fig. 3. Double staining for HSP47 and -SMA in the same section from a representative patient with chronic allograft rejection. Note that HSP47- (brown) positive cells are also positive for -SMA (blue) (arrowhead). Magnification: (A) x200, (B) x600.

 

View larger version (10K): [in this window] [in a new window]   Fig. 4. Relationship between expression of HSP47 and that of -SMA (A), the number of CD68-positive cells (B) and type I collagen (C). (a) The percentages of areas positively stained for HSP47, -SMA and type I collagen were calculated by a computer image analyser and the number of CD68-positive cells was counted. The degree of HSP47 expression correlated with that of -SMA, type I collagen and the number of CD68-positive cells in the interstitial areas. Data represent the Pearsons' rank coefficients. (b) P<0.001.

 
Localization of collagen type I in normal and allograft kidneys
Staining for type I collagen was very weak in some interstitial cells of normal and 1 h post-transplantation kidneys (data not shown). In contrast, a strong expression of collagen type I was noted in the interstitium of renal tissues with chronic allograft rejection or CsA toxicity (Figure 2D). When the distribution pattern of type I collagen was compared with that of HSP47 (Figure 2E) and -SMA (Figure 2F) in adjacent sections, type I collagen was localized mainly in the interstitium where the cells expressing HSP47 were present. Furthermore, the distribution of cells positive for type I collagen was also similar to that of -SMA in the area of interstitial fibrosis. Image analysis showed a significant correlation between the expression of HSP47 and type I collagen in the interstitial area of allograft rejection (Figure 4C).

Correlation between expression of HSP47 and degree of interstitial fibrosis in renal allograft rejection
Computer image analysis of the interstitium demonstrated that the expression of HSP47 and -SMA significantly correlated with the score of interstitial fibrosis (Figure 5A and B). In addition, positive correlation was also observed between the number of CD68-positive cells and the score of interstitial fibrosis (Figure 5C).

View larger version (8K): [in this window] [in a new window]   Fig. 5. Relationship between the degree of interstitial fibrosis and expression of HSP47 (A), -SMA (B) and the number of CD68-positive cells (C). (a) We calculated the percentage of areas positively stained for HSP47 and -SMA using a computer image analyser and counted the number of CD68-positive cells. The scale used to define the degree of interstitial fibrotic change is explained in Materials and methods. Interstitial expression of HSP47, -SMA and the number of CD68-positive cells correlated significantly with the degree of tubulointerstitial fibrotic change. Data are Spearman's rank correlation coefficients. (b) P<0.001.

 

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

 
The major findings of the present study were the detection of HSP47 in the interstitial area and that its expression correlated with the degree of interstitial fibrosis. We also found the expression of HSP47 in glomerular sclerosis present in human allograft rejection kidney (data not shown). These findings support the notion that HSP47 plays an important role in the pathogenesis of fibrosis of chronic rejection.

It is important to identify the exact type of cells producing collagen in interstitial fibrosis of transplanted kidney, although the exact site of collagen production remains controversial. In the present study, we demonstrated that HSP47 was localized in interstitial fibroblasts and renal tubular epithelial cells. Previous in vitro studies have shown that fibroblasts and renal tubular epithelial cells produce collagen protein and mRNA [18,19]. Furthermore, in situ hybridization studies demonstrated localization of collagen mRNA in interstitial fibroblasts in rats [20,21] and human renal tissues [22]. Considering the fact that HSP47 specifically binds to newly synthesized procollagen [5], these results indicate that fibroblasts and tubular epithelial cells are the predominant sites of collagen production in the tubulointerstitium of chronic rejection renal tissues. In fact, the distribution pattern of HSP47 expression was similar to that of type I collagen in the present study. Furthermore, our results demonstrating that the level of HSP47 expression correlated with the histological degree of fibrosis indicate that increased expression of HSP47 is associated with increased collagen production.

With regard to the expression pattern of HSP47 in chronic renal allograft rejection, there was no difference between chronic allograft rejection and CsA toxicity. This observation suggests that HSP47 may be mechanistically linked to the common fibrotic pathway observed in both types of allograft rejection.

In the tubulointerstitium, the majority of spindle-shaped cells positive for HSP47 were also positive for -SMA. Boukhalfa et al. [16] recently have demonstrated a positive correlation between interstitial up-regulation of -SMA and the degree of interstitial fibrosis in various forms of glomerulonephritis. Since -SMA is regarded as a marker of activated fibroblasts, myofibroblasts [23], it is possible that the transformation of fibroblasts into myofibroblasts is a key step in the process that leads to increased production of collagen. The exact factors involved in the transformation of fibroblasts into myofibroblasts remain to be identified. In the present study, several cells positive for CD68 were found around cells positive for -SMA and HSP47 in the interstitium. Furthermore, interstitial expression of -SMA and HSP47 correlated with the number of CD68-positive mononuclear cells. These findings suggest that infiltrating macrophages may be involved in the transformation of fibroblasts to myofibroblasts and in collagen production. Although the exact role of macrophages in such a transformation process was not fully investigated in the present study, certain growth factors secreted from macrophages may induce fibroblast transformation. With regard to this, Desmouliere et al. [24] demonstrated that transforming growth factor-ß (TGF-ß) mediates the attainment of myofibroblast features including -SMA expression by cultured skin fibroblasts. Furthermore, Tang et al. [25] showed that infusion of platelet-derived growth factor (PDGF) induced tubulointerstitial myofibroblast formation in rats. In fact, infiltrating macrophages produce TGF-ß [26] and PDGF [27] in certain pathological conditions. Thus, the results of these early studies together with the present findings suggest that infiltrating macrophages may play a key role in the transformation of fibroblasts into myofibroblasts by secreting cytokines and growth factors. Further studies are warranted in order to understand the association between macrophages and myofibroblasts. Our study also showed that -SMA-positive myofibroblasts expressed HSP47, indicating that these cells are actively involved in the production of collagen during the process of fibrosis. Indeed, in vitro studies have demonstrated that the amount of collagen I, III and IV secreted by myofibroblasts in diseased kidneys is 4- to 5-fold higher than that by fibroblasts in normal renal tissues [19].

Since HSP47 is a stress protein, determination of the exact factors that induce HSP47 in the chronic rejected kidney is also important. Although Hosokawa et al. [28] reported the presence of a heat shock element in the HSP47 promoter, the factors binding to the element have not yet been determined. Further studies are necessary to determine those factors that induce HSP47. Interestingly, Sunamoto et al. [11] recently showed that inhibition of HSP47 expression by antisense oligonucleotides caused down-regulation of collagen synthesis in experimental glomerulonephritis induced by anti-Thy-1 antibodies. This finding provides direct evidence that the chaperone molecule associated with collagen production can control the production itself, pointing to a possible therapeutic application against fibrogenesis. Thus, by controlling the expression of HSP47, it may be possible to control the production of collagen.

In conclusion, the present study demonstrated that HSP47 is expressed in interstitial -SMA-positive myofibroblasts and tubular epithelial cells in fibrotic renal allograft tissue samples. Our results also indicated the involvement of HSP47 and an important role for infiltrating macrophages in the pathogenesis of tubulointerstitial fibrosis in the transplanted kidney.

	Acknowledgments

 
We are grateful to Tomomi Nakamura for her technical assistance and Yukiko Abe for her assistance and preparation of the manuscript. This study was supported in part by grants from the Ministry of Health and Welfare of Japan.

	References

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Received for publication: 15. 2.99
Accepted in revised form: 16.11.99

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