nach oben

Erschienen in:

01.06.2007 | Original Article

Pax-2 and N-myc regulate epithelial cell proliferation and apoptosis in a positive autocrine feedback loop

verfasst von: Shao-Ling Zhang, Yun-Wen Chen, Stella Tran, Fang Liu, Eirini Nestoridi, Marie-Josée Hébert, Julie R. Ingelfinger

Erschienen in: Pediatric Nephrology | Ausgabe 6/2007

Einloggen, um Zugang zu erhalten

Abstract

Both paired homeo box-2 (Pax-2) and N-myc genes play pivotal roles in renal morphogenesis via their effects on cell proliferation and differentiation, but whether and how they interact have not been addressed. In the present study, we investigated such a potential interaction using embryonic renal cells in vitro. Mouse embryonic mesenchymal (MK4) cells stably transfected with Pax-2 cDNA in sense (+) or antisense (−) orientation were used for experiments. Pax-2 promoter activity was monitored by luciferase assay. Reactive oxygen species (ROS) generation, cell proliferation, and cell apoptosis were evaluated. We found that Pax-2 and N-myc gene expression were upregulated and downregulated in Pax-2 (+) and Pax-2 (−) stable transformants, respectively. ROS generation and apoptosis were significantly reduced both in Pax-2 (+) transformants compared with Pax-2 (−) transformants and in naïve MK4 cells cultured in either normal- (5 mM) or high-glucose (25 mM) medium. Transient transfection of N-myc cDNA into Pax-2 (−) stable transformants restored Pax-2 gene expression and prevented ROS generation induced by high glucose. Our data demonstrate that Pax-2 gene overexpression prevents hyperglycemia-induced apoptosis, and N-myc appears to provide a positive autocrine feedback on Pax-2 gene expression in embryonic mesenchymal cells.

Piscione TD, Rosenblum ND (1999) The malformed kidney: disruption of glomerular and tubular development. Clin Genet 56:341–356PubMed

Piscione TD, Rosenblum ND (2002) The molecular control of renal branching morphogenesis: current knowledge and emerging insights. Differentiation 70:227–246PubMed

Ardissino G, Dacco V, Testa S, Bonaudo R, Claris-Appiani A, Taioli E, Marra G, Edefonti A, Sereni F (2003) Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics 111:e382–e387PubMed

Seikaly MG, Ho PL, Emmett L, Fine RN, Tejani A (2003) Chronic renal insufficiency in children: the 2001 Annual Report of the NAPRTCS. Pediatr Nephrol 18:796–804PubMed

Kitzmiller JL, Gavin LA, Gin GD, Jovanovic-Peterson L, Main EK, Zigrang WD (1991) Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 265:731–736PubMed

Lynch SA, Wright C (1997) Sirenomelia, limb reduction defects, cardiovascular malformation, renal agenesis in an infant born to a diabetic mother. Clin Dysmorphol 6:75–80PubMed

Soler NG, Walsh CH, Malins JM (1976) Congenital malformations in infants of diabetic mothers. Q J Med 45:303–313PubMed

Woolf AS (1997) Multiple causes of human kidney malformations. Arch Dis Child 77:471–473PubMedPubMedCentral

Brenner BM, Garcia DL, Anderson S (1988) Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1:335–347PubMed

10.

Brenner BM, Mackenzie HS (1997) Nephron mass as a risk factor for progression of renal disease. Kidney Int (Suppl) 63:S124–S127

11.

Mackenzie HS, Brenner BM (1995) Fewer nephrons at birth: a missing link in the etiology of essential hypertension? Am J Kidney Dis 26:91–98PubMed

12.

Mackenzie HS, Lawler EV, Brenner BM (1996) Congenital oligonephropathy: The fetal flaw in essential hypertension? Kidney Int (Suppl) 55:S30–S34

13.

Kanwar YS, Nayak B, Lin S, Akagi S, Xie P, Wada J, Chugh SS, Danesh FR (2005) Hyperglycemia: its imminent effects on mammalian nephrogenesis. Pediatr Nephrol 20:858–866PubMed

14.

Kanwar YS, Akagi S, Nayak B, Sun L, Wada J, Xie P, Thakur A, Chugh SS, Danesh FR (2005) Renal-specific oxidoreductase biphasic expression under high glucose ambience during fetal versus neonatal development. Kidney Int 68:1670–1683PubMed

15.

Amri K, Freund N, Van Huyen JP, Merlet-Benichou C, Lelievre-Pegorier M (2001) Altered nephrogenesis due to maternal diabetes is associated with increased expression of IGF-II/mannose-6-phosphate receptor in the fetal kidney. Diabetes 50:1069–1075PubMed

16.

Eccles MR (1998) The role of PAX2 in normal and abnormal development of the urinary tract. Pediatr Nephrol 12:712–720PubMed

17.

Bouchard M, Souabni A, Mandler M, Neubuser A, Busslinger M (2002) Nephric lineage specification by Pax2 and Pax8. Genes Dev 16:2958–2970PubMedPubMedCentral

18.

Dressler GR, Deutsch U, Chowdhury K, Nornes HO, Gruss P (1990) Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Development 109:787–795PubMed

19.

Dressler GR, Wilkinson JE, Rothenpieler UW, Patterson LT, Williams-Simons L, Westphal H (1993) Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature 362:65–67PubMed

20.

Dziarmaga A, Quinlan J, Goodyer P (2006) Renal hypoplasia: lessons from Pax2. Pediatr Nephrol 21:26–31PubMed

21.

Dziarmaga A, Hueber PA, Iglesias D, Hache N, Jeffs A, Gendron N, Mackenzie A, Eccles M, Goodyer P (2006) Neuronal apoptosis inhibitory protein (NAIP) is expressed in developing kidney and is regulated by PAX2. Am J Physiol Renal Physiol 291:F913–F920PubMed

22.

Dziarmaga A, Eccles M, Goodyer P (2006) Suppression of ureteric bud apoptosis rescues nephron endowment and adult renal function in Pax2 mutant mice. J Am Soc Nephrol 17:1568–1575PubMed

23.

Torres M, Gomez-Pardo E, Dressler GR, Gruss P (1995) Pax-2 controls multiple steps of urogenital development. Development 121:4057–4065PubMed

24.

Brophy PD, Ostrom L, Lang KM, Dressler GR (2001) Regulation of ureteric bud outgrowth by Pax2-dependent activation of the glial derived neurotrophic factor gene. Development 128:4747–4756PubMed

25.

Torban E, Dziarmaga A, Iglesias D, Chu LL, Vassilieva T, Little M, Eccles M, Discenza M, Pelletier J, Goodyer P (2006) PAX2 activates WNT4 expression during mammalian kidney development. J Biol Chem 281:12705–12712PubMed

26.

Dziarmaga A, Clark P, Stayner C, Julien JP, Torban E, Goodyer P, Eccles M (2003) Ureteric bud apoptosis and renal hypoplasia in transgenic PAX2-Bax fetal mice mimics the renal-coloboma syndrome. J Am Soc Nephrol 14:2767–2774PubMed

27.

Eccles MR, He S, Legge M, Kumar R, Fox J, Zhou C, French M, Tsai RW (2002) PAX genes in development and disease: the role of PAX2 in urogenital tract development. Int J Dev Biol 46:535–544PubMed

28.

Porteous S, Torban E, Cho NP, Cunliffe H, Chua L, McNoe L, Ward T, Souza C, Gus P, Giugliani R, Sato T, Yun K, Favor J, Sicotte M, Goodyer P, Eccles M (2000) Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +/− mutant mice. Hum Mol Genet 9:1–11PubMed

29.

Favor J, Sandulache R, Neuhauser-Klaus A, Pretsch W, Chatterjee B, Senft E, Wurst W, Blanquet V, Grimes P, Sporle R, Schughart K (1996) The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Proc Natl Acad Sci USA 93:13870–13875PubMedPubMedCentral

30.

Maeshima A, Maeshima K, Nojima Y, Kojima I (2002) Involvement of Pax-2 in the action of activin A on tubular cell regeneration. J Am Soc Nephrol 13:2850–2859PubMed

31.

Salomon R, Tellier AL, Attie-Bitach T, Amiel J, Vekemans M, Lyonnet S, Dureau P, Niaudet P, Gubler MC, Broyer M (2001) PAX2 mutations in oligomeganephronia. Kidney Int 59:457–462PubMed

32.

Erdosova B, Wagner F, Kylarova D (2004) The detection of MYC proteins in the developing human kidney. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 148:205–207PubMed

33.

Semsei I, Ma SY, Cutler RG (1989) Tissue and age specific expression of the myc proto-oncogene family throughout the life span of the C57BL/6J mouse strain. Oncogene 4:465–471PubMed

34.

Patterson LT, Dressler GR (1994) The regulation of kidney development: new insights from an old model. Curr Opin Genet Dev 4:696–702PubMed

35.

Bates CM, Kharzai S, Erwin T, Rossant J, Parada LF (2000) Role of N-myc in the developing mouse kidney. Dev Biol 222:317–325PubMed

36.

Valerius MT, Patterson LT, Witte DP, Potter SS (2002) Microarray analysis of novel cell lines representing two stages of metanephric mesenchyme differentiation. Mech Dev 112:219–232PubMed

37.

Zhang SL, Moini B, Ingelfinger JR (2004) Angiotensin II increases Pax-2 expression in fetal kidney cells via the AT2 receptor. J Am Soc Nephrol 15:1452–1465PubMed

38.

Zhang SL, Guo J, Moini B, Ingelfinger JR (2004) Angiotensin II stimulates Pax-2 in rat kidney proximal tubular cells: impact on proliferation and apoptosis. Kidney Int 66:2181–2192PubMed

39.

Nestoridi E, Kushak RI, Duguerre D, Grabowski EF, Ingelfinger JR (2005) Up-regulation of tissue factor activity on human proximal tubular epithelial cells in response to Shiga toxin. Kidney Int 67:2254–2266PubMed

40.

Chen YW, Liu F, Tran S, Zhu Y, Hebert MJ, Ingelfinger JR, Zhang SL (2006) Reactive oxygen species and nuclear factor-kappa B pathway mediate high glucose-induced Pax-2 gene expression in mouse embryonic mesenchymal epithelial cells and kidney explants. Kidney Int 70:1607–1615PubMed

41.

Tokunaga K, Taniguchi H, Yoda K, Shimizu M, Sakiyama S (1986) Nucleotide sequence of a full-length cDNA for mouse cytoskeletal beta-actin mRNA. Nucleic Acids Res 14:2829PubMedPubMedCentral

42.

Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS (2002) High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology 143:2975–2985PubMed

43.

Hsieh TJ, Fustier P, Wei CC, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Fantus IG, Hamet P, Chan JS (2004) Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells. J Endocrinol 183:535–550PubMed

44.

Gnarra JR, Dressler GR (1995) Expression of Pax-2 in human renal cell carcinoma and growth inhibition by antisense oligonucleotides. Cancer Res 55:4092–4098PubMed

45.

Muratovska A, Zhou C, He S, Goodyer P, Eccles MR (2003) Paired-box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22:7989–7997PubMed

46.

Torban E, Eccles MR, Favor J, Goodyer PR (2000) PAX2 suppresses apoptosis in renal collecting duct cells. Am J Pathol 157:833–842PubMedPubMedCentral

47.

Imgrund M, Grone E, Grone HJ, Kretzler M, Holzman L, Schlondorff D, Rothenpieler UW (1999) Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1. Kidney Int 56:1423–1431PubMed

48.

Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMed

49.

Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625PubMed

Titel: Pax-2 and N-myc regulate epithelial cell proliferation and apoptosis in a positive autocrine feedback loop
verfasst von: Shao-Ling Zhang
Yun-Wen Chen
Stella Tran
Fang Liu
Eirini Nestoridi
Marie-Josée Hébert
Julie R. Ingelfinger
Publikationsdatum: 01.06.2007
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Nephrology / Ausgabe 6/2007
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-007-0444-z

Neu im Fachgebiet Pädiatrie

23.04.2024 | Typ-1-Diabetes | Nachrichten

Update Pädiatrie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Pax-2 and N-myc regulate epithelial cell proliferation and apoptosis in a positive autocrine feedback loop

Abstract

Neu im Fachgebiet Pädiatrie

Neuer Typ-1-Diabetes bei Kindern am Wochenende eher übersehen

Neue Studienergebnisse zur Myopiekontrolle mit Atropin

Spinale Muskelatrophie: Neugeborenen-Screening lohnt sich

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

Update Pädiatrie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2007

Is there a role for rituximab in the treatment of idiopathic childhood nephrotic syndrome?

Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate

Predictive value of clinical and laboratory variables for vesicoureteral reflux in children

The malnutrition and inflammation axis in pediatric patients with chronic kidney disease

Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells

NOx (nitrite/nitrate) in patients with pediatric nephrotic syndrome

Neu im Fachgebiet Pädiatrie

Neuer Typ-1-Diabetes bei Kindern am Wochenende eher übersehen

Neue Studienergebnisse zur Myopiekontrolle mit Atropin

Spinale Muskelatrophie: Neugeborenen-Screening lohnt sich

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

Update Pädiatrie