PAX2, a homeotic gene of ‘paired box family’, is a nuclear transcription factor expressed in mesenchymal/epithelial conversion during the early stages of nephrogenesis; however, its repression is necessary for terminal differentiation of mature tubular cells. Transgenic overexpression in animal model causes epithelial hyperproliferation and microcyst formation. In humans, PAX2 expression has been observed in cystic and dysplasic tubular epithelia in kidney malformation and in kidney disease. We have investigated PAX2 expression and its colocalization with cytokeratin and/or vimentin in 17 biopsies of juvenile nephronophthisis (NPH), an autosomal-recessive renal disease characterized by diffuse renal fibrosis and occasional cysts. Fourteen cases were analyzed for deletion and mutation in the NPH1 gene locus and 33% resulted to be deleted or mutated; for the remaining cases the diagnosis was based on clinical and pathological criteria. The control group included 4 congenital dysplastic kidneys, and 10 biopsies of nephropathies with secondary chronic tubulointerstitial damage. In all cases of renal dysplasia a strong nuclear positivity was observed in immature tubules surrounded by αSMA-positive mesenchymal cells. In NI biopsies the tubular epithelia were almost PAX2 negative, although tubulointerstitial damage was severe. In 14/17 NPH1 moderate-to-strong nuclear PAX2 positivity of tubular cells was observed, particularly in cystic distal tubules located at the corticomedullary junction, but also in proximal tubular sections. The PAX2 signal co-localized more with cytokeratin staining than with vimentin. Our results confirm the observation of PAX2 expression in immature dysplastic tubules and its repression in mature renal tubular cells, also in the presence of severe secondary interstitial fibrosis. PAX2 seems to be overexpressed in NPH. The genetic defect of NPH, a disease probably due to a primary defect along the cascade of mesenchymal epithelial differentiation, could generate a functionally abnormal protein involved in focal adhesion signaling and cell/matrix interaction. The failure of PAX2 repression or its reactivation in NPH could be a marker of hyperproliferation and incomplete maturation of epithelial tubular cells, probably due to a defect cell/matrix cross-talk, and involved in interstitial fibrosis and cysts formation.

Keywords:
PAX2, Nephronophthisis, Renal biopsy, Immunohistochemistry
1.
Dressler G: The genetic control of renal development. Curr Opin Nephrol Hypertens 1995;4:253–257.
2.
Ekblom P: Genetics of kidney development. Curr Opin Nephrol Hypertens 1996;5:282–287.
3.
Mansouri A, Hallonet M, Gruss P: Pax genes and their roles in cell differentiation and development. Curr Opin Cell Biol 1996;8:851–857.
4.
Eccles MR: The role of Pax2 in normal and abnormal development of the urinary tract. Pediatr Nephrol 1998;12:712–720.
5.
Rothenpieler UW, Dressler GR: Pax2 is required for mesenchyme-to-epithelium conversion during kidney development. Development (Camb) 1993;119:711–720.
6.
Torban E, Goodyer P: What PAX genes do in the kidney. Exp Nephrol 1998;6:7–11.
7.
Eccles MR, Schimmenti LA: Renal-coloboma syndrome: A multi-system developmental disorder caused by PAX2 mutations. Clin Genet 1999;56:1–9.
8.
Dressler GR, Wilkinson UW, Rothenpieler LT, Patterson L, Williams-Simons, Westphal H: Deregulation of PAX2 expression in transgenic mice generates severe kidney abnormalities. Nature (Lond) 1993;362:65–67.
9.
Winyard PJD, Ridson RA, Sams VR, Dressler GR, Woolf AS: The PAX2 transcription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations. J Clin Invest 1996;98:451–459.
10.
Eng E, Wilson PD, Racusen LC, Burrowe CR: Aberrant Pax-2 expression in human autosomal polycystic kidney disease (APKD) epithelia (abstract). J Am Soc Nephrol 1994;5:621.
11.
Hildebrandt F, Waldherr R, Kutt R, Brandis M: The nephronophthisis complex: Clinical and genetics aspects. Clin Invest 1992;70:802–808.
12.
Konrad M, Saunier S, Heidt L, Silbermann F, Benessy F, Calado J, Le Paslier D, Broyer M, Gubler MC, Antignac C: Large homozygous deletions of the 2q13 region are major cause of juvenile nephronophthisis. Hum Mol Genet 1996;5:367–371.
13.
Caridi G, Murer L, Bellantuono R, Sorino P, Caringella DA, Gusmano R, Ghiggeri GM: Renal-retinal syndromes: Association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of NPH1 locus. Am J Kidney Dis 1998;32:1059–1062.
14.
Caridi G, Dagnino M, Gusmano R, Ginevri F, Murer L, Ghio L, Piaggio G, Ciardi MR, Perfumo F, Ghiggeri GM: Clinical and molecular heterogeneity of juvenile nephronophthisis in Italy: Insights from molecular screening. Am J Kidney Dis 2000;35:44–51.
15.
Wolf DC, Whiteley HE, Everitt JI: Preneoplastic and neoplastic lesions of rat hereditary renal cell tumors express markers of proximal and distal nephron. Vet Pathol 1995;32:379–386.
16.
Hay ED, Zuk A: Transformations between epithelium and mesenchyme: Normal, pathological and experimentally induced. Am J Kidney Dis 1995;26:678–690.
17.
Torban E, Goodyer PR: Effects of Pax2 expression in a human fetal kidney (HEK293) cell line. Biochim Biophys Acta 1998;1401:53–62.
18.
Dressler GR: Pax2, kidney development and oncogenesis. Med Pediatr Oncol 1996;27:440–444.
19.
Remuzzi G, Bertani T: Pathophysiology of progressive nephropathies. N Engl J Med 1998;339:1448–1456.
20.
Fine LG, Norman JT, Ong A: Cell-cell cross talk in the pathogenesis of renal interstitial fibrosis. Kidney Int 1995;47:549–550.
21.
Strutz F: The fibroblast: A (trans)differentiated cell? Nephrol Dial Transplant 1995;10:1504–1506.
22.
Hildebrandt F, Waldherr R, Kutt R, Brandis M: The nephronophthisis complex: Clinical and genetic aspects. Clin Invest 1992;70:802–808.
23.
Rahilly MA, Fleming S: Abnormal integrin receptor expression in two cases of familial nephronophthisis. Histopathology 1995;26:345–349.
24.
Antignac C, Arduy C, Beckmann J, Benessy F, Gros F, Medhiboub M, Hildebrandt F, Dufier JL, Kleineknecht C, Broyer M, Weissenbach J, Habib R, Cohen D: A gene for familial juvenile nephronophthisis (recessive medullary cystic disease) maps to chromosome 2p. Nat Genet 1993;3:342–345.
25.
Hildebrandt F, Singh-Sawhney I, Schnieders B, Centofante L, Omran H, Pohlmann A, Schmaltz C, Wedekind H, Schubotz C, Antignac C: Mapping of gene for familial juvenile nephronophthisis: Refining the map and defining flanking markers on chromosome 2. APN Study Group. Am J Hum Genet 1993;53:1256–1261.
26.
Hildebrandt F, Otto E, Rensing C, Nothwang HG, Vollmer M, Adolphs J, Hanusch H, Brandis M: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 1997;17:149–153.
27.
Otto E, Kispert A, Schaltzle, Lescher B, Rensing C, Hildebrandt F: Nephrocystin: Gene expression and sequence conservation between human, mouse, and Caenorhabditis elegans. J Am Soc Nephrol 2000;11:270–282.
28.
Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG: PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet 1997;14:179–183.
29.
Hildebrandt F: Identification of a gene for nephronophthisis. Nephrol Dial Transplant 1998;13:1334–1336.
30.
Lodish H, Baltimore D, Berk A, Zirpusky SL, Matsudaira P, Darnell J: Molecular Cell Biology. New York, Freeman, 1995, p 65.
31.
Lo SH, Yu QC, Degenstein L, Chen LB, Fuchs E: Progressive kidney degeneration in mice lacking tensin. J Cell Biol 1997;136:1349–1361.
32.
Hildebrandt F, Otto E: Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol 2000;11:1753–1761.
33.
Birchmeier W, Birchmeier C: Mesenchymal-epithelial transitions. BioEssays 1994;16:305–307.
34.
Yorioka N, Taniguchi Y, Yamshita K, Usui K, Shigemoto K, Harada S, Taguchi T, Yamakido M: Hepatocyte growth factor in nephronophthisis-medullary cystic disease complex. Pediatr Nephrol 1996;10:515–516.
© 2002 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.