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Hypothesis Accepted: January 7, 2000

Nephron 2000;86:339–341

Heat Shock Protein 47 in Renal Scarring M.S. Razzaque a, b N. Ahsan b T. Taguchi a a 2nd

Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan; of Nephrology, Pennsylvania State University College of Medicine, Hershey, Pa., USA

b Division

Key Words Heat shock protein 47 W Collagen W Renal scarring

Abstract Heat shock protein 47 (HSP47) is a collagen-binding protein, thought to play an essential mechanistic role in the assembly and processing of procollagens. HSP47 is increasingly being implicated in the pathogenesis of several human and experimental fibrotic diseases. HSP47 could mediate increased accumulation of collagens in the fibrotic mass, possibly by regulating increased assembly of procollagens. Therefore, modulation of HSP47 might be a valuable tool for manipulation of some fibrotic diseases, including renal scarring Copyright © 2000 S. Karger AG, Basel

Introduction

Increased deposition of various types of collagen is a typical feature in the development of renal fibrosis. Clarification of the molecular mechanisms underlying fibrotic disorders and the development of effective therapy are both of clinical importance. It has been shown that heat shock protein 47 (HSP47) is an important collagen-specific stress protein and possibly involved in the assembly

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and secretion of procollagens and that, as a consequence, it may play a pivotal role in the fibrotic changes that follow tissue damage in many vital organs, including liver, lung, and kidney.

Heat Shock Protein 47

Environmental, chemical, or physiological stress induces the expression of a group of highly conserved proteins called heat shock proteins (HSPs). The cellular response to stress was discovered by Ritossa [1, 2], and so far, at least two general roles of HSPs have been suggested for helping cells cope with stress-induced protein damage. Some HSPs can promote degradation of abnormal proteins, whereas others can reactivate stress-damaged proteins by preventing the aggregation or by promoting the proper refolding of denatured proteins [3]. HSP47, a 47-kD stress protein, is localized on the endoplasmic reticulum of collagen-producing cells and is thought to participate in procollagen processing as a collagen-specific chaperone. Kurkinen et al. [4] first identified a collagen-binding protein from murine parietal endodermal cells and found it to bind specifically to collagens. Thereafter, species-specific collagen-binding proteins were characterized in human and rat as gp46 [5, 6], in the chick as HSP47 [7], and in the mouse as J6 [8].

M.S. Razzaque, MBBS, PhD Division of Nephrology, Pennsylvania State University College of Medicine Hershey Medical Center, PO Box 850 H040 Hershey, PA 17033 (USA) E-Mail razzaque@net.nagasaki-u.ac.jp


The formation of a triple-helical structure is one of the important posttranslational events in the collagen synthesis. In the endoplasmic reticulum, HSP47 binds to the alpha polypeptide chains, possibly to assist in the alignment and folding of the triple helix. Afterwards, HSP47 dissociates from the procollagen molecule once it enters the Golgi apparatus [9, 10]. Substantial in vitro evidence now points to HSP47 as a collagen-specific chaperone that assists in the intracellular processing, alignment, folding, and/or assembly of procollagens. Here we will discuss the possible in vivo role of HSP47 in human and experimental renal fibrotic diseases.

HSP47 and the Kidney

HSP47 and Experimental Glomerular Scarring Early inflammatory reactions cause proliferation and activation of glomerular cells, which, without intervention, ultimately lead to progressive glomerular scarring. In experimental nephritis induced by antithymocyte serum, an increased glomerular expression of HSP47 was associated with increased deposition of collagens in the scleroproliferative glomeruli [11]. Furthermore, within the scleroproliferative glomeruli, colocalization study revealed that phenotypically altered collagen-producing glomerular myofibroblasts (alpha-smooth muscle actin positive) were the main source of HSP47. Also, in the rat antiGBM (glomerular basement membrane) autoimmune glomerulonephritis model, marked accumulation of HSP47 was seen in developing and sclerosing crescents. Since HSP47 is a molecular chaperone that is intimately involved in synthesizing procollagen, we suggest that increased levels of glomerular HSP47 may regulate synthesis and assembly of the various procollagens and thus contribute to the glomerular sclerotic process. HSP47 and Experimental Tubulointerstitial Scarring The progression of tubulointerstitial fibrosis is characterized by the appearance of interstitial myofibroblasts that express alpha-smooth muscle actin [12], and tubular epithelial cells expressing vimentin [13] with interstitial inflammatory cell infiltration. Earlier studies have convincingly shown that increased synthesis of collagens by interstitial myofibroblasts and tubular epithelial cells results in tubulointerstitial fibrosis. In rat models, an increased expression of HSP47 was consistently observed in the interstitial myofibroblasts and tubular epithelial cells during the process of experimental and spontaneous tubulointerstitial fibrosis [14–16]. Increased expression of

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HSP47 was seen in and around areas of interstitial fibrosis, and it colocalizes with collagens (types I and III). In these areas, infiltrating monocytes/macrophages (ED-1 positive) in the interstitium did not express HSP47. HSP47 and Human Sclerotic/Fibrotic Diseases Few studies deal with the expression of HSP47 in the normal human adult kidney [17]. However, in adult human kidneys HSP47 has been detected at very low levels in intraglomerular cells, tubular epithelial cells, and interstitial cells. HSP47 was strongly expressed in proliferating mesangial cells in human IgA nephropathy, diabetic kidneys, and during crescentic glomerulonephritis. In all types of nephropathy studied, HSP47 was strongly expressed in the tubular epithelial cells and in alphasmooth muscle actin positive myofibroblastic cells associated with areas of interstitial scarring [17, 18]. Available data suggest that irrespective of primary disease, upregualtion of HSP47 was seen during collagenization of glomeruli and tubulointerstitium [17].

Modulating HSP47 for Therapeutic Purposes

Calorie restriction has been known not only to suppress spontaneous neoplasms [19], but also to reduce the spontaneous age-associated renal scarring [20, 21]. The increased expression of HSP47 was closely associated with age-associated renal scarring in Fischer 344 rats. Furthermore, calorie restriction suppressed HSP47 expression and was associated with improvement of renal scarring [21]. In experimental nephritis models, the inhibition of HSP47 overexpression by administration of HSP47 antisense oligodeoxynucleotides resulted in the suppression of collagen production. Furthermore, this treatment attenuated the histological manifestations of glomerulosclerosis [22]. The results of both these in vivo studies [21, 22] raise the possibility of beneficial effects of therapeutic intervention interfering with HSP47 in renal fibrotic diseases. Blocking the relatively early factors for cell proliferation (i.e, platelet-derived growth factor) and matrix synthesis (i.e., transforming growth factor beta) has been shown to have some beneficial effects on the renal fibrotic process. However, HSP47 is playing a role in the later stage of collagen biosynthesis. Thus, targeting HSP47 could have a greater chance to reverse the fibrotic course, even in the later stages of the process.

Razzaque/Ahsan/Taguchi


Conclusions

Renal fibrosis accounts for considerable chronic morbidity in various renal diseases and could be a target of therapy. Since HSP47 plays a role in the fibrotic process [11, 14–17, 23–26] it will be of interest to determine whether monitoring HSP47 expression might have a predictive value in defining patients at risk of developing renal fibrotic complications and in assessing the response to conventional therapy. In addition, devising therapeutic

strategies directed at interfering with the HSP47 could be beneficial. As preliminary studies [21, 22] have shown, suppressing the expression of HSP47 can modulate renal scarring.

Acknowledgment We thank Dr. Jacqueline M. Crisman for critical reading and insightful comments on the manuscript.

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Heat Shock Protein 47 in Renal Scarring

11 Razzaque MS, Taguchi T: Collagen-binding heat shock protein (HSP) 47 expression in antithymocyte serum (ATS)-induced glomerulonephritis. J Pathol 1997;183:24–29. 12 Muchaneta-Kubara EC, el Nahas AM: Myofibroblast phenotype expression in experimental renal scarring. Nephrol Dial Transplant 1997; 12:904–915. 13 Nakatsuji S, Yamate J, Sakuma S: Relationship between vimentin expressing renal tubules and interstitial fibrosis in chronic progressive nephropathy in aged rats. Virchows Arch 1998; 433:359–367. 14 Razzaque MS, Taguchi T: Localization of HSP47 in cisplatin-treated rat kidney: A possible role in tubulointerstitial damage. Clin Exp Nephrol 1999;3:222–228. 15 Razzaque MS, Shimokawa I, Nazneen A, Higami Y, Taguchi T: Age-related nephropathy in the Fischer 344 rat is associated with overexpression of collagens and collagen-binding heat shock protein 47. Cell tissue Res 1998;293: 471–478. 16 Cheng M, Razzaque MS, Nazneen A, Taguchi T: Expression of the heat shock protein 47 in gentamicin-treated rat kidneys. Int J Exp Pathol 1998;79:125–132. 17 Razzaque MS, Kumatori A, Harada T, Taguchi T: Coexpression of collagens and collagenbinding heat shock protein 47 in human diabetic nephropathy and IgA nephropathy. Nephron 1998;80:434–443. 18 Nakahama H, Nakamura H, Kitada O, Sugita M: Chronic drug-induced tubulointerstitial nephritis with renal failure associated with propylthiouracil therapy. Nephrol Dial Transplant 1999;14:1263–1265.

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19 Hursting SD, Perkins SN, Brown CC, Haines DC, Phang JM: Calorie restriction induces a p53-independent delay of spontaneous carcinogenesis in p53-deficient and wild-type mice. Cancer Res 1997;57:2843–2846. 20 Maeda H, Gleiser CA, Masoro EJ, Murata I, McMahan CA, Yu BP: Nutritional influences on aging of Fischer 344 rats. II. Pathology. J Gerontol 1985;40:671–688. 21 Razzaque MS, Shimokawa I, Nazneen A, Liu D, Naito T, Higami Y, Taguchi T: Life-long dietary restriction modulates the expression of collagens and collagen-binding heat shock protein 47 in aged Fisher 344 rat kidney. Histochem J 1999;31:123–132. 22 Sunamoto M, Kuze K, Tsuji H, Ohishi N, Yagi K, Nagata K, Kita T, Doi T: Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis. Lab Invest 1998;78:967–972. 23 Razzaque MS, Nazneen A, Taguchi T: Immunolocalization of collagen and collagen-binding heat shock protein 47 in fibrotic lung diseases. Modern Pathol 1998;11:1183–1188. 24 Kawada N, Kuroki T, Kobayashi K, Inoue M, Nakatani K, Kaneda K, Nagata K: Expression of heat-shock protein 47 in mouse liver. Cell Tissue Res 1996;284:341–346. 25 Razzaque MS, Taguchi T: The possible role of colligin/HSP47, a collagen-binding protein, in the pathogenesis of human and experimental fibrotic diseases. Histol Histopathol 1999;14: 1199–1212. 26 Razzaque MS, Hossain MA, Kohno S, Taguchi T: Bleomycin-induced pulmonary fibrosis in rat is associated with increased expression of collagen-binding heat shock protein (HSP) 47. Virchows Arch 1998;432:455–460.

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