Apoptosis in Polycystic Kidney Disease
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Increased Apoptosis and Proliferative Capacity are Early Events in Cyst Formation in Autosomal Dominant Polycystic Kidney Disease Salwa Ibrahim, MD, Msc (Nephrology), MRCP (UK) Assistant Professor of Medicine and Nephrology Cairo University, Egypt The ScientificWorld JOURNAL (2007) 7, 1757–1767
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5/9/2009 2 Background In autosomal-dominant, polycystic kidney disease (ADPKD), the genetic defect results in the growth of a multitude of epithelial cysts within the renal parenchyma The protein products of PKD genes (polycystin-1 and polycystin-2) are thought to function together as part of a multiprotein, membrane-spanning complex involved in cell-cell-matrix interactions
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5/9/2009 3 Background Polycystin-1 and -2 can initiate signal transduction, leading to activation of a number of downstream effectors that regulate the cell cycle events, including cell proliferation and apoptosis Progressive deterioration in renal function is also associated with a build up of inflammatory monocytes and macrophages within renal interstitium around expanding cysts and subsequent interstitial fibrosis
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5/9/2009 4 MATERIAL AND METHODS Human tissues were obtained from 16 adult patients with ADPKD (seven females and nine males) The tissue sections were obtained from the archival material of the Department of Pathology at the Northern General Hospital, Sheffield, UK and all were nephrectomy sections All cases had been routinely formalin fixed and paraffin embedded Details of these patients are listed in Table 1
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5/9/2009 6 Detection of Epithelial Proliferation by Monoclonal Antibody to PCNA Proliferation was detected using monoclonal antibody against proliferating cell nuclear antigen (PCNA) (clone PC10, 1:50 dilution, Dako, U.K.) For antigen retrieval, either simple heating at 95°C for 15 min or a microwave pre-treatment method as suggested by Shi et al. was used with slight modification Immunolocalization of epithelial cells expressing EMA, which is a distal nephron, distal convoluted tubule, and collecting duct marker was performed using monoclonal antibodies to EMA (1:300, Dako, U.K.)
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5/9/2009 7 In situ End Labelling for the Detection of Apoptotic Cells In histological sections, fragmented nuclear DNA associated with apoptosis were labelled in situ with digoxigenin-deoxyuridine (dUTP), introduced by terminal deoxynucleotidyl transferase (TdT), according to standard method described by Gavrieli et al. using ApopTag® peroxidase in situ apoptosis detection kit (Intergen, Oxford, U.K.).
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5/9/2009 8 Immunohistochemical Staining for Interstitial Mononuclear Cells Immunostaining for CD 68– and CD 45–positive cells was performed using mouse antihuman CD 68 and CD 45 monoclonal antibodies diluted to 1:200 (Dako-Dakopatts, Denmark) Mononuclear interstitial infiltration was assessed by counting the number of CD 45– and CD 68–positive cells in 20 randomly chosen 0.25 × 0.25 mm areas of tubulointerstitum in each section
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5/9/2009 9 (A) PCNA-positive nucleus in hyperplastic epithelium of a cyst(B) PCNA-positive nuclei in epithelium lining of a cystic tubule (C) PCNA-positive nuclei in epithelium lining a noncystic tubule (D) PCNA-positive nuclei in the interstitium around a noncystic tubule
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5/9/2009 10 (E) Apoptotic cell (arrow) within the hyperplastic epithelial cells lining a cyst (F) Apoptotic cell in the epithelial lining a cystic tubule (arrow) and in the surrounding interstitium (arrowhead)
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5/9/2009 11 (G) Apoptotic cell in the epithelial lining a noncystic tubule (arrow) and in the surrounding interstitium (arrowhead)(H) A cluster of apoptotic cells located in the interstitium (arrows)
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5/9/2009 12 (I) Dense interstitial infiltration with CD 68–positive macrophages (using anti CD 68 antibodies)(J) Dense interstitial infiltration with CD 45–positive lymphocytes (using anti CD 45 antibodies)
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5/9/2009 13 (K) Densely stained hyperplastic epithelium of a cyst using antibodies to EMA. (L) A cyst lined with atrophic epithelium showed negative EMA staining
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5/9/2009 14 The PI values of the epithelium lining the cysts, cystic tubules, and noncystic tubules were 18- to 39-fold higher than the respective normal control group (p < 0.0005)
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5/9/2009 15 The AI values of the epithelial lining of cysts, cystic tubules, noncystic tubules, and the interstitium were markedly increased compared with the control group (P = 0.001)
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5/9/2009 16 CONCULSIONS The PI value was substantially higher in the epithelium lining the noncystic tubules and was 39-fold higher than the control (P < 0.0005) The PI value of the epithelial cells lining noncystic tubules was higher than that of the cyst (p < 0.001) The PI of the epithelium lining the cystic tubules was 30-fold higher than the control (P< 0.0005), while that of cyst was about 18-fold higher than the control (P=0.0001) No consistent correlation with a specific epithelial morphology was detected, as cysts with hyperplastic-layered epithelium did not display higher PI than that of those with attenuated atrophic cell lining
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5/9/2009 17 CONCULSIONS One of the key findings in this study was the demonstration of a significant increased interstitial PI that was about 190-fold higher than the control (P < 0.0005) The interstitial infiltrates were dense and consisted mainly of CD 68–positive macrophages and CD 45–positive lymphocytes (p < 0.005) This interstitial inflammation reflects one of the basic fundamental features that is common to all species of PKD Progressive deterioration in renal function is associated with a buildup of inflammatory monocytes and macrophages within the renal interstitium around the expanding cysts
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5/9/2009 18 CONCULSIONS In this study, the apoptotic index was significantly increased in the epithelium lining noncystic tubules and was 29-fold higher than the corresponding control value (p < 0.0005) A high AI was also significantly increased in the epithelium lining cystic structures, although to a lesser degree (p = 0.001) Similarly, the interstitial apoptotic score was significantly higher than that of the control (29.7-fold, p < 0.0005), and was located either as single cells or in clusters adjacent to the noncystic and cystic structures
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5/9/2009 19 CONCULSIONS Epithelial and interstitial cellular proliferation was coupled with increased apoptosis with the predominance of the former However, there was no significant correlation between the degree of apoptosis and proliferation in each renal compartment An equal proportion of cysts and cystic tubules were either EMA positive or negative with some cysts showing a heterogeneous staining pattern with variable intensity These findings are consistent with previous observations that ADPKD cysts may originate from any nephron segment
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5/9/2009 20 References Sullivan, L.P., Wallace, D.P., and Grantham, J.J. (1998) Epithelial transport in polycystic kidney disease. Physiol. Rev. 78(4), 1165–1191 Nadasdy, T., Laszik, Z., Lajoie, G., et al. (1995) Proliferative activity of cyst epithelium in human renal cystic diseases. J. Am. Soc. Nephrol. 5, 1462–1468 Lanoix, J., D’Agati, V., Szabolcs, M., et al. (1996) Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). Oncogene 13, 1153–1160 Ramasubbu, K., Gretz, N., and Bachmann, S. (1997) Increased epithelial cell proliferation and abnormal extracellular matrix in rat polycystic kidney disease. J. Am. Soc. Nephrol. 9, 937–945 Calvet, J.P. and Grantham, J.J. (2001) The genetics and physiology of polycystic kidney disease. Semin. Nephrol. 2, 107–123 Woo, D. (1995) Apoptosis and loss of renal tissue in polycystic kidney diseases. N. Engl. J. Med. 333, 18–25 Winyard, P.J., Nauta, J., Lirenman, D., et al. (1996) Deregulation of cell survival in cystic and dysplastic renal development. Kidney Int. 49, 135–146.
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