Network Analysis of a -Mouse Model of Autosomal Dominant Polycystic Kidney Disease Identifies HNF4α as a Disease Modifier

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Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095) leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation and cyst formation by applying transcriptomics and metabolomics to follow disease progression in a large number of animals induced before P10. Weighted gene co-expression network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. Knowledge-based Ingenuity Pathway Analysis (IPA) software identifies HNF4α as a likely network node. These results are further supported by a meta-analysis of 1,114 published gene expression arrays in Pkd1 wild-type tissues. These analyses also predict that metabolic pathways are key elements in postnatal kidney maturation and early steps of cyst formation. Consistent with these findings, urinary metabolomic studies show that Pkd1 cystic mutants have a distinct profile of excreted metabolites, with pathway analysis suggesting altered activity in several metabolic pathways. To evaluate their role in disease, metabolic networks were perturbed by inactivating Hnf4α and Pkd1. The Pkd1/Hnf4α double mutants have significantly more cystic kidneys, thus indicating that metabolic pathways could play a role in Pkd1-cystogenesis.

Vyšlo v časopise: Network Analysis of a -Mouse Model of Autosomal Dominant Polycystic Kidney Disease Identifies HNF4α as a Disease Modifier. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003053
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003053

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Zdroje

1. TorresV, HarrisP, PirsonY (2007) Autosomal dominant polycystic kidney disease. Lancet 369: 1287–1301.

2. MenezesL, GerminoG (2009) Polycystic kidney disease, cilia, and planar polarity. Methods Cell Biol 94: 273–297.

3. PiontekK, HusoD, GrinbergA, LiuL, BedjaD, et al. (2004) A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J Am Soc Nephrol 15: 3035–3043.

4. PiontekK, MenezesL, Garcia-GonzalezM, HusoD, GerminoG (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13: 1490–1495.

5. Lantinga-van LeeuwenIS, LeonhardWN, van der WalA, BreuningMH, de HeerE, et al. (2007) Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum Mol Genet 16: 3188–3196.

6. DavenportJR, WattsAJ, RoperVC, CroyleMJ, van GroenT, et al. (2007) Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol 17: 1586–1594.

7. VerdeguerF, Le CorreS, FischerE, CallensC, GarbayS, et al. (2010) A mitotic transcriptional switch in polycystic kidney disease. Nat Med 16: 106–110.

8. FalkG (1955) Maturation of renal function in infant rats. Am J Physiol 181: 157–170.

9. AbuazzaG, BeckerA, WilliamsS, ChakravartyS, TruongH, et al. (2006) Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins. Am J Physiol Renal Physiol 291: F1132–1141.

10. BeckerA, ZhangJ, GoyalS, DwarakanathV, AronsonP, et al. (2007) Ontogeny of NHE8 in the rat proximal tubule. Am J Physiol Renal Physiol 293: F255–261.

11. LangfelderP, HorvathS (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9: 559.

12. BarabásiAL, GulbahceN, LoscalzoJ (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12: 56–68.

13. GonzalezFJ (2008) Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet 23: 2–7.

14. LiX, MagenheimerBS, XiaS, JohnsonT, WallaceDP, et al. (2008) A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease. Nat Med 14: 863–868.

15. ChapmanAB, TorresVE, PerroneRD, SteinmanTI, BaeKT, et al. (2010) The HALT polycystic kidney disease trials: design and implementation. Clin J Am Soc Nephrol 5: 102–109.

16. TorresV, WangX, QianQ, SomloS, HarrisP, et al. (2004) Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 10: 363–364.

17. LangfelderP, HorvathS (2007) Eigengene networks for studying the relationships between co-expression modules. BMC Syst Biol 1: 54.

18. OldhamM, HorvathS, GeschwindD (2006) Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc Natl Acad Sci U S A 103: 17973–17978.

19. PastorelliL, WellsS, FrayM, SmithA, HoughT, et al. (2009) Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract. Mamm Genome 20: 140–151.

20. PandeyP, BrorsB, SrivastavaP, BottA, BoehnS, et al. (2008) Microarray-based approach identifies microRNAs and their target functional patterns in polycystic kidney disease. BMC Genomics 9: 624.

21. PandeyP, QinS, HoJ, ZhouJ, KreidbergJA (2011) Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease. BMC Syst Biol 5: 56.

22. LeeS, MasyukT, SplinterP, BanalesJ, MasyukA, et al. (2008) MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J Clin Invest 118: 3714–3724.

23. AllenE, PiontekK, Garrett-MayerE, Garcia-GonzalezM, GorelickK, et al. (2006) Loss of polycystin-1 or polycystin-2 results in dysregulated apolipoprotein expression in murine tissues via alterations in nuclear hormone receptors. Hum Mol Genet 15: 11–21.

24. TakiarV, NishioS, Seo-MayerP, KingJD, LiH, et al. (2011) Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A 108: 2462–2467.

25. Tanguay RM, Marie L, Markus G, A MG (2011) Hypertyrosinemia. In: Valle, Beaudet, Vogelstein, Kinzler, Antonarakis, et al.., editors. Scriver's Online Metabolic and Molecular Bases of Inherited Disease.

26. YamaguchiT, PellingJ, RamaswamyN, EpplerJ, WallaceD, et al. (2000) cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int 57: 1460–1471.

27. YamaguchiT, WallaceD, MagenheimerB, HempsonS, GranthamJ, et al. (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279: 40419–40430.

28. ChalmersRA, RoeCR, StaceyTE, HoppelCL (1984) Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine. Pediatr Res 18: 1325–1328.

29. BöhmN, UyJ, KiesslingM, LehnertW (1982) Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Eur J Pediatr 139: 60–65.

30. HussonH, ManavalanP, AkmaevV, RussoR, CookB, et al. (2004) New insights into ADPKD molecular pathways using combination of SAGE and microarray technologies. Genomics 84: 497–510.

31. SongX, Di GiovanniV, HeN, WangK, IngramA, et al. (2009) Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum Mol Genet 18: 2328–2343.

32. ChenW, TzengY, LiH (2008) Gene expression in early and progression phases of autosomal dominant polycystic kidney disease. BMC Res Notes 1: 131.

33. ChenWS, ManovaK, WeinsteinDC, DuncanSA, PlumpAS, et al. (1994) Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev 8: 2466–2477.

34. LiJ, NingG, DuncanSA (2000) Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev 14: 464–474.

35. ParvizF, MatulloC, GarrisonWD, SavatskiL, AdamsonJW, et al. (2003) Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34: 292–296.

36. BattleMA, KonopkaG, ParvizF, GagglAL, YangC, et al. (2006) Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci U S A 103: 8419–8424.

37. GarrisonWD, BattleMA, YangC, KaestnerKH, SladekFM, et al. (2006) Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology 130: 1207–1220.

38. HayhurstG, LeeY, LambertG, WardJ, GonzalezF (2001) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21: 1393–1403.

39. AhnSH, ShahYM, InoueJ, MorimuraK, KimI, et al. (2008) Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis 14: 908–920.

40. RheeJ, GeH, YangW, FanM, HandschinC, et al. (2006) Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism. J Biol Chem 281: 14683–14690.

41. AdamsonAW, SuchankovaG, RufoC, NakamuraMT, Teran-GarciaM, et al. (2006) Hepatocyte nuclear factor-4alpha contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase. Biochem J 399: 285–295.

42. DankelSN, HoangT, FlågengMH, SagenJV, MellgrenG (2010) cAMP-mediated regulation of HNF-4alpha depends on the level of coactivator PGC-1alpha. Biochim Biophys Acta 1803: 1013–1019.

43. HayhurstGP, Strick-MarchandH, MuletC, RichardAF, MorosanS, et al. (2008) Morphogenetic competence of HNF4 alpha-deficient mouse hepatic cells. J Hepatol 49: 384–395.

44. KanazawaT, IchiiO, OtsukaS, NamikiY, HashimotoY, et al. (2011) Hepatocyte nuclear factor 4 alpha is associated with mesenchymal-epithelial transition in developing kidneys of C57BL/6 mice. J Vet Med Sci 73: 601–607.

45. VincentSD, RobertsonEJ (2004) Targeted insertion of an IRES Cre into the Hnf4alpha locus: Cre-mediated recombination in the liver, kidney, and gut epithelium. Genesis 39: 206–211.

46. TaylorSL, GantiS, BukanovNO, ChapmanA, FiehnO, et al. (2010) A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease. Am J Physiol Renal Physiol 298: F909–922.

47. AbbissH, MakerGL, GummerJ, SharmanMJ, PhillipsJK, et al. (2012) Development of a non-targeted metabolomics method to investigate urine in a rat model of polycystic kidney disease. Nephrology (Carlton) 17: 104–110.

48. HsuPP, SabatiniDM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134: 703–707.

49. BolettaA (2009) Emerging evidence of a link between the polycystins and the mTOR pathways. Pathogenetics 2: 6.

50. WeiQ, BhattK, HeH, MiQ, HaaseV, et al. (2010) Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 21: 756–761.

51. Rasband WS (1997–2011) Imagej, U.S. National Institues of Health, Bethesda, MD, USA.

52. GentlemanR, CareyV, BatesD, BolstadB, DettlingM, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80.

53. DuP, KibbeW, LinS (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24: 1547–1548.

54. LinS, DuP, HuberW, KibbeW (2008) Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36: e11.

55. JohnsonW, LiC, RabinovicA (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8: 118–127.

56. ZhangB, HorvathS (2005) A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4: Article17.

57. KanehisaM, GotoS (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30.

58. SmithCA, O'MailleG, WantEJ, QinC, TraugerSA, et al. (2005) METLIN: a metabolite mass spectral database. Ther Drug Monit 27: 747–751.