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Heat Shock Protein 47 in Chronic Allograft Nephropathy Abstract

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hronic allograft nephropathy (CAN), associated with late allograft dysfunction is caused by alloantigen‑dependent and ‑independent mechanisms that eventually progresses to irreversible interstitial fibrosis. Heat shock protein 47 (HSP47) is a collagen‑specific molecular chaperone and is closely associated with progression of fibroproliferative lesions in various organs, by facilitating increased production of collagens; a correlation between the increased expression of HSP47 and extent of interstitial fibrosis is found in the biopsy tissues obtained from patients with CAN. The activation of complement cascade is a poor prognostic indicator of graft survival; a correlation between the expression of C4d (a marker of complement activation) and HSP47 has also been noted in renal biopsy tissues of patients with CAN. ��������������������������������������������������� A detailed and comprehensive review of all aspects of interstitial fibrosis in patients with CAN����������������������������� �������������������������������� is beyond the scope of this chapter; rather we will briefly summarize the lessons learned from recent studies on roles of HSP47 during the progression of fibrotic diseases and its possible implication in CAN.

Chronic Allograft Nephropathy (CAN)

Our understanding of immunological mechanisms and availability of new effective immunosuppressants has significantly diminished the incidence of renal allograft dysfunction during the early postrenal trans‑ plantation period. However, no such dramatic improvement has been made with regard to the incidence of late allograft dysfunction. CAN is usually associated with progressive decline in glomerular filtration rate, in conjunction with proteinuria and arterial hypertension and is believed to be ���������������������������������������������������� the single most common cause of long‑term allograft failure.� In ����������������������������������������������������������������� this chapter, the term CAN is mostly used to describe the non‑ specific morphologic changes in chronically dysfunctioning allografts. In the majority of the patients with histological evidence of CAN, a linear relationship usually exists between the time of diagnosis of CAN and the deterioration of renal allograft function.1‑3 ����������������� The pathological changes in CAN, which are classified according to the Banff classifica‑ tion,4 could be alloantigen‑dependent and/or alloantigen‑independent phenomena and usually progress to irreversible interstitial fibrosis. A �� better understanding of cellular ������������������������������������������ and molecular events of CAN will provide the specific therapeutic targets and/or options to intervene the progression of interstitial fibrosis. Peritubular capillary (PTC) deposition of C4d reflects comple‑ ment activation via the classical pathway 5 and represents a trace of the remaining alloantibodies;6 presence of C4d is considered to be a reli‑ able marker of antibody‑mediated allograft rejection. C4d is a suitable

marker of acute humoral rejection;7,8 studies have also documented C4d in renal allograft biopsies with morphologic features of chronic rejection.9 Presence of C4d in a ������������������������������������� substantial number cases reemphasize the fact that immunologically mediated chronic renal allograft rejec‑ tion is indeed the major cause of CAN. The ������������������������������� capillary C4d staining has also found to be associated with poor graft survival.10‑12 Interestingly, a correlation between the renal expression of C4d and HSP47 (a mol‑ ecule that helps in intracellular maturation of collagens) has also been documented in CAN.13

Heat Shock Protein 47 (HSP47)

Heat shock proteins (HSPs) provide cellular defense against a wide range of injuries; a number of HSPs are constitutively expressed and actively involved in maintaining cellular homeostasis, by acting as molecular chaperones.14‑16 HSPs in mammalian cells are transcription‑ ally regulated by the heat shock transcription factor (HSF), which can selectively bind to the heat shock promoter element (HSE).17,18 In normal, unstressed cells, HSF is present in the cytoplasm, but under stressful microenvironment, HSF converts from an inactive monomeric form to an active trimeric DNA‑binding form, which then translocates to the nucleus and interacts with HSE to induce transcription of HSP genes19,20 (Fig. 1). Recently, HSP47, a collagen‑binding molecular chaperone, has found to be involved in the molecular maturation of procollagen molecules. Collagen‑binding molecular chaperone was first charac‑ terized from murine parietal endoderm cells and was termed as col‑ ligin.21 Subsequent studies from different laboratories have identified species‑specific collagen‑binding proteins in human and rat as gp46,22 in the mouse as J623 and in the chick and rabbit as HSP47;24,25 all these proteins were later found to be the same group of molecules with a com‑ mon collagen binding abilities and now generally refers as HSP47. Collagen biosynthesis is a complex multi‑step process that has both intracellular and extracellular events; the synthesis of the alpha polypep‑ tide chains, their hydroxylation and formation of stable triple‑helical procollagen molecules are intracellular events of collagen synthesis. HSP47, a 47‑kDa glycoprotein protein, resides in the endoplasmic reticulum (ER) of collagen‑producing cells and help in the assembly and correct folding of triple helical procollagen molecules,26 which is eventually transported to the extracelluar space across the Golgi com‑ plex, where N and C propeptides are cleaved by procollagen N‑ and C‑ proteinases to assemble into collagen fibrils.27,28 An in vivo essential role of HSP47 in collagen synthesis and subsequent organogenesis has been demonstrated in hsp47 knockout mice; ablation of hsp47 from

*Corresponding Author: � M. ��� Shawkat �������� Razzaque—Department ����������������������� of Developmental �������������� Biology, ��������� Harvard �������� School ���������� of Dental ������� Medicine, ���������� Research and Educational Building, Room: 304, 190 Longwood Avenue, Boston, MA 02115, USA. Email: mrazzaque@hms.harvard.edu

Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management, edited by Nasimul Ahsan. ©2007 Landes Bioscience.

©2007 Copyright Landes Bioscience. Not for Distribution

Takashi Taguchi and Mohammed Shawkat Razzaque*


Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management

Figure 1. Simplified diagram illustrating the regulation of heat shock proteins (HSPs). Heat shock transcription factors (HSF) are normally bound to HSPs as inactive molecules in the cytosol. Upon exposure to stressors, HSFs are phosphorylated (P) by protein kinases, rapidly form trimmers and translocate to the nucleus where HSFs interact with heat shock promoter element (HSE) to induce the transcription of HSPs, which are then transcribed and relocate to the cytosol. We have only included the essential steps of regulation of HSP to keep the diagram simple.

mouse genome has resulted in abnormal collagen formation and im‑ paired organogenesis. Complete ablation of hsp47 from the mouse was embryonically lethal and knockout mice died prenatally at embryonic 11.5 day.29 These studies suggest that, in absence of HSP47, there is abnormal molecular maturation of its substrate protein, collagen. In fibrotic diseases, it is expected that by targeting HSP47, it might be possible to generate unstable collagen which is more likely to degrade and thereby reducing accumulation of collagen in the fibrotic mass.

HSP47 and Fibrotic Diseases

One of the common features of pathologic tissue scarring is excessive accumulation of matrix proteins due to uncontrolled synthesis and/or degradation.30‑32 Most of the fibrotic diseases are progressive in nature and gradual expansion of fibrotic mass eventually leads to the destruc‑ tion of normal structure of the affected tissues; the size and extent of fibrotic mass usually influence the functionality of the affected organs and uncontrolled fibrosis progresses to end‑stage organ failure. A close association between increased expression of HSP47 and deposition of collagens has been documented in fibrotic diseases affecting various human and experimental animals.33‑40 For instance, antithymocyte serum (ATS)‑induced nephritis, is a widely used experimental model of mesangial cell proliferation and glomerulosclerosis;33 an increased glomerular expression of HSP47 has found to be closely associated with excessive accumulation of collagens in the scleroproliferative glomeruli;33 phenotypically altered collagen producing glomerular myofibroblasts (a‑smooth muscle actin positive) and glomerular epithe‑ lial cells (desmin‑positive) are the main HSP47‑producing cells in the sclerotic glomeruli.33,34,41 Blocking, in vivo, the bioactivities of HSP47 by treating the nephritic animals with antisense oligodeoxynucleotides against HSP47 could delay the progression of glomerulosclerosis.42 These studies provide an experimental basis of why we believe that increased expression of HSP47 in fibrotic diseases is pathogenic rather than an epiphenomenon. Since HSP47 is intimately involved in the molecular maturation of procollagens, it is likely that high levels of

glomerular HSP47 might help in increased production of collagens, and thus contribute to the glomerular sclerotic process. A similar induction in the expression of HSP47 and excessive accumulation of collagens in the glomeruli was also noted in other experimental models of glomerulosclerosis, including in hypertensive nephrosclerosis (Fig. 2) and diabetic nephropathy.39,43 The exact molecular mechanism of renal tubulointerstitial fibrosis is not yet clear and is believed to be characterized by interstitial accu‑ mulation of collagens, produced by phenotypically altered interstitial cells and tubular epithelial cells. Expression of a‑smooth muscle actin (a‑SMA) in renal interstitial cells is indicative of acquiring myofibro‑ blastic phenotype, while expression of intermediate filament vimentin in tubular epithelial cells is suggestive of phenotypical alteration of renal tubular epithelial cells. Studies have demonstrated that increased synthesis of interstitial collagens by phenotypically altered interstitial myofibroblasts and tubular epithelial cells play an important role in the initiation and progression of tubulointerstitial fibrotic process in various experimental models of tubulointerstitial fibrosis, including in cisplatin nephropathy, aged‑associated nephropathy and hypertensive nephrosclerosis.35,41,44‑47 In these above‑mentioned experimental models, elevated expression of HSP47 was often associated with excessive ac‑ cumulation of collagens in areas around the interstitial fibrosis. A very few studies have examined the role of HSP47 in human fibrotic diseases. The first such human study was conducted using renal biopsy tissues of IgA nephropathy and diabetic nephropathy.48 In adult human kidneys, expression of HSP47 was very weak. In contrast, enhanced expression of HSP47 was detected in the early sclerotic glom‑ eruli of IgA nephropathy and diabetic nephropathy. HSP47 was also expressed in tubulointerstitial cells in areas around interstitial fibrosis in both IgA nephropathy and diabetic nephropathy.48 The glomerular and tubulointerstitial expression of HSP47 in renal biopsy tissues was closely associated with glomerular accumulation of type IV collagen and interstitial accumulation of types I and III collagens, respectively.

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Figure 2. Immunohistochemical expression of HSP47 in normotensive (A) and hypertensive (B) Dahl rat kidneys. Compared to normotensive rats, there is increased expression of HSP47 in the glomerulus of hypertensive rats (arrows). Note increased expression of HSP47 also in the thickened blood vessels in the hypertensive kidney (arrows). It is presumed that increased expression of HSP47 in the hypertensive kidney is associated with eventual nephrovascular sclerosis, by facilitating increased production of collagens.

One of the unique features of HSP47 is that its overexpression is consistently observed in all the studied fibrotic diseases involving the lung, liver, heart, eye and skin.24,36‑40,49‑60 It appears likely that ir‑ respective of primary diseases, upregulation of HSP47 is a common phenomenon during collagenization of the involved tissues/organs. It is therefore reasonable to speculate that monitoring the expression of HSP47 might help in defining those patients at risk for developing fibrotic complications and in assessing the response to the conventional and selective therapies in various fibrotic diseases, including in patients with CAN.

Role of C4d and HSP47 in CAN

The possible roles of HSP47 in developing the tubulointerstitial fibrotic lesions in patients with CAN need comprehensive studies. Preliminary studies, however, suggest a potential ����������������� role of HSP47 in CAN; an association between the expression of C4d and HSP47 in the renal biopsy tissues, obtained from the patients with CAN has been reported. Recently, in a study that comprised 48 renal allografts (30 male, 18 women; 45 living related donors and 3 cadaveric origin), were

retrospectively analyzed for the renal expression of C4d and HSP47.13 C4d was very weakly detected in the PTC cells of the control kidney, in contrast, in 16 out of 48 (33.3%) patients, C4d deposition was detected along endothelial cells of PTC; C4d expression significantly correlated with the presence of proteinuria (p = 0.002) in these group of patients. Moreover, the level of serum creatinine in C4d‑positive patients was significantly higher than in C4d‑negative patients (p = 0.004). More importantly, as expected, C4d staining correlated significantly with subsequent graft loss (p = 0.004). When the expression of C4d was related to Banff classification,4 the C4d‑positive cases were found to have advanced histological features of interstitial fibrosis and tubular atrophy than C4d‑negative cases.13 In the same group of patients, the correlation analysis showed that the median proportion of cell area posi‑ tive for HSP47 in C4d‑positive group of patients (average 2.70%) was significantly higher (p = 0.038) than in C4d‑negative group (average 1.64%). Moreover, an association between the enhanced expressions of C4d and HSP47 has been detected in renal biopsy sections of patients with CAN; the interstitial expression of HSP47 was mostly located in and around C4d‑positive PTCs in the interstitium. These observations,

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Heat Shock Protein 47 in Chronic Allograft Nephropathy


Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management

though preliminary, suggest a possible role of HSP47 in the pathogen‑ esis of CAN. In addition, compared to control, increased interstitial expression of TGF‑b1���������������������������������������������������� , a well‑know fibrogenic factor was also detected in the renal biopsy sections positive for C4d stained patients with CAN.13 This study has clearly demonstrated an association between the expression of C4d and HSP47 in patients with CAN. Further studies with larger population of patients with various stages of disease process will be needed to define the role of HSP47 in CAN; at this stage HSP47 appears to have a fibrogenic role in patients with CAN. C4d is a complement split product generated through complement degradation, activated by antigen‑antibody complexes; it is considered as an indicator of humoral activity in allografts and is a useful marker of humoral immunoreaction.61,62 In recent reports, capillary deposition of C4d was identified in 30‑34% of allograft biopsies6 and chronic rejection seems to be distinguished from alloantigen‑independent CAN by C4d staining. Furthermore, Mróz et al62 reported that specific histological changes of chronic rejection, such as chronic transplant glomerulopathy and/or arterial intimal thickening with lymphocyte infiltration, were present in about 83% of C4d‑positive cases and that such deposits were noted in PTC, again suggesting that staining of C4d in the biopsy tissue is a specific marker for the rejection process.62 In recent reports, capillary deposition of C4d was recommended as a marker of CAN caused by immunological reaction (chronic rejection), although the exact role of C4d remains unclear.6,7,62 HSP47, a collagen‑binding protein that binds with newly synthe‑ sized procollagen and its overexpression correlates with tubulointer‑ stitial fibrosis, a morphological feature of CAN that result in renal dysfunction. Recent studies have shown that HSP47 is produced by activated fibroblasts and myofibroblasts, the main cell types that are also responsible for increased synthesis of collagens during fibrosis in various organs.38,39,47,50 The transformation of fibroblasts to myofibro‑ blasts and infiltration of macrophages are common features of CAN; these infiltrating and transformed cells are source of fibrogenic factors including TGF‑b1 and platelet‑derived growth factor (PDGF) to regulate interstitial fibrosis in CAN.63,64 TGF‑b1 mediates the attainment of myofibroblast features including a‑SMA expression by cultured skin fibroblasts 65 and PDGF‑induced tubulointerstitial myofibroblast formation in experimental animals.66 In a recent study, an increased numbers of CD68‑positive macrophages, TGF‑b1‑positive cells and a‑SMA‑positive interstitial cells were de‑ tected in renal biopsy sections of patients with CAN that was positive for C4d staining in PTC; the results of this study and those of previ‑ ous studies suggest that the immunopathological changes of CAN is mostly association with C4d deposition in PTC; moreover, infiltration of macrophages and production of TGF‑b1 and PDGF might help in transforming myofibroblast in the tubulointerstitium of patients with CAN. The activated interstitial cells, including myofibroblasts could produce an increased level of HSP47 and TGF‑b1; both these fibrogenic molecules could induce excessive synthesis and interstitial accumulation of collagen in CAN, by regulating transcriptional and posttranslational processing of collagens. Furthermore, increased expression of TGF‑b1 might in turn could induce the expression of HSP47 in CAN; recent in vitro studies have shown such induction of HSP47 by TGF‑b1.67‑69 Since inhibition of HSP47 expression in fibrotic models resulted in less fibrogenic changes in the affected organs,70,71 similar approach might help in preventing or delaying the progression of tubulointerstitial fibrosis in patients with CAN.

Clinical Potential of HSP47 As an Antifibrotic Target

Despite a number of important fibrogenic molecules that have been identified in recent years, most of these molecules are not for suitable therapeutic targets because of their widespread vital systemic effects. In addition, regardless of the in vitro efficacy, some of the circulating

fibrogenic molecules were not effective in the complex in vivo micro‑ environment. Since HSP47 is involved in the molecular maturation of collagens, a selective blockade of its activities in fibrotic diseases might be clinically useful. In vivo suppression of HSP47 expression by the administration of antisense oligodeoxynucleotides against HSP47 delayed the progression of glomerular sclerotic process by reducing glomerular accumulation of collagens in rats with experimental ne‑ phritis.42 Similar antifibrotic response using antisense HSP47 therapy has shown to be effective in reducing wound‑related scarring.70,71 These preliminary observations suggest a profibrotic role of HSP47 and more importantly, provide the in vivo evidence of HSP47 as a potential antifibrotic therapeutic target;42,70 a phenomenon that has enormous clinical importance and applicability in a wide range of fibrotic diseases, including in CAN.

Conclusion

How feasible HSP therapy is for clinical use? It is particularly useful in various neurodegenerative disorders, where aberrant protein aggre‑ gation and neuron degeneration are the common pathologic features; induction of HSPs, particularly HSP70 by gene transfer can reduce the aberrant protein misfolding and inhibit the apoptotic deletion of cells to attenuate dopaminergic neuron degeneration in Parkinson’s dis‑ ease.72 Recent understanding of structural basis of the HSP47‑collagen interaction can also form the conceptual templates for possible drug designing by taking the advantage of pharmacophore‑based strate‑ gies.73‑75 In contrast to most, if not all of the, molecular chaperones that recognize several target proteins, HSP47 has a single substrate protein, collagen. HSP47, therefore, provides a very selective target to manipulate collagen production, a phenomenon that might have enormous clinical application in controlling fibrotic diseases, including CAN. Preliminary observations suggest a strong rationale for blocking the bioactivities of collagen‑binding HSP47, as one of the options to control the progression of fibrotic diseases;76 further controlled in vivo studies to determine both favorable and adverse effects of blocking the bioactivities of HSP47.

Acknowledgements

We are grateful to Miss Kanako Egashira for her assistance in prepar‑ ing of histological sections. Part of this chapter is based on a recently published review article, entitled, “The collagen‑specific molecular chaperone HSP47: is there a role in fibrosis?” in the journal “Trends in Molecular Medicine”. Our apology goes to the authors whose original work might be inadvertently oversighted from the reference list.

References

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Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management

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