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PMID: 20436483 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.

Nature medicine ·Vol. 16 ·No. 5 ·2010-05-00 ·Pages 535-43, 1p following 143

Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV

Abstract

Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.

MeSH Terms
Acute Kidney Injury/genetics Adult Cell Cycle Epithelial Cells/metabolism Fibrosis Glomerulonephritis/genetics Humans Kidney/metabolism,pathology Kidney Diseases/genetics,pathology Mitogen-Activated Protein Kinase 9/metabolism Tumor Suppressor Protein p53/metabolism
Chemicals
Tumor Suppressor Protein p53 Mitogen-Activated Protein Kinase 9
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yang Li
Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Besschetnova Tatiana Y
Brooks Craig R
Shah Jagesh V
Bonventre Joseph V
References (52)
52 references, click to expand
  1. Intrinsic epithelial cells repair the kidney after injury.
    Cell Stem Cell. 2008 Mar 6;2(3):284-91 PMID: 18371453
  2. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.
    Am J Kidney Dis. 2003 Jan;41(1):1-12 PMID: 12500213
  3. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury.
    Am J Physiol Renal Physiol. 2004 Mar;286(3):F552-63 PMID: 14600030
  4. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.
    Nature. 2009 Aug 27;460(7259):1140-4 PMID: 19668186
  5. Cellular and molecular mechanisms of fibrosis.
    J Pathol. 2008 Jan;214(2):199-210 PMID: 18161745
  6. Up-regulation of cell cycle regulatory genes after renal ischemia/reperfusion: differential expression of p16(INK4a), p21(WAF1/CIP1) and p27(Kip1) cyclin-dependent kinase inhibitor genes depending on reperfusion time.
    Transpl Int. 2006 Jan;19(1):72-7 PMID: 16359379
  7. The cell cycle and acute kidney injury.
    Kidney Int. 2009 Sep;76(6):604-13 PMID: 19536080
  8. Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-beta-induced mouse fibrosis.
    J Cell Physiol. 2008 Sep;216(3):680-7 PMID: 18481257
  9. Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases.
    Mol Cell Biol. 2002 Feb;22(3):874-85 PMID: 11784863
  10. Stathmin-deficient mice develop fibrosis and show delayed recovery from ischemic-reperfusion injury.
    Am J Physiol Renal Physiol. 2006 Jun;290(6):F1559-67 PMID: 16434570
  11. Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure.
    J Am Soc Nephrol. 2003 Jun;14 Suppl 1:S55-61 PMID: 12761240
  12. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy.
    Science. 1999 Sep 10;285(5434):1733-7 PMID: 10481009
  13. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity.
    Nature. 2009 Aug 27;460(7259):1149-53 PMID: 19668189
  14. ATM activation and signaling under hypoxic conditions.
    Mol Cell Biol. 2009 Jan;29(2):526-37 PMID: 18981219
  15. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM.
    Cancer Res. 2004 Dec 15;64(24):9152-9 PMID: 15604286
  16. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis.
    J Am Soc Nephrol. 2005 Jan;16(1):133-43 PMID: 15574513
  17. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.
    J Clin Invest. 2008 May;118(5):1657-68 PMID: 18414680
  18. The assessment of cellular proliferation by immunohistochemistry: a review of currently available methods and their applications.
    Histochem J. 1992 Mar;24(3):121-31 PMID: 1349881
  19. The lack of a functional p21(WAF1/CIP1) gene ameliorates progression to chronic renal failure.
    Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10830-5 PMID: 10485911
  20. Requirement for p53 and p21 to sustain G2 arrest after DNA damage.
    Science. 1998 Nov 20;282(5393):1497-501 PMID: 9822382
  21. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.
    Nature. 2009 Aug 27;460(7259):1132-5 PMID: 19668191
  22. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition.
    J Biol Chem. 2007 Aug 10;282(32):23337-47 PMID: 17562716
  23. Regulation and pathological role of p53 in cisplatin nephrotoxicity.
    J Pharmacol Exp Ther. 2008 Nov;327(2):300-7 PMID: 18682572
  24. Ischemic acute renal failure: long-term histology of cell and matrix changes in the rat.
    Kidney Int. 2000 Jun;57(6):2375-85 PMID: 10844607
  25. Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis.
    Cytokine Growth Factor Rev. 2008 Apr;19(2):133-44 PMID: 18358427
  26. Protection of renal epithelial cells against oxidative injury by endoplasmic reticulum stress preconditioning is mediated by ERK1/2 activation.
    J Biol Chem. 2003 Aug 1;278(31):29317-26 PMID: 12738790
  27. Regulation of the G2/M transition by p53.
    Oncogene. 2001 Apr 5;20(15):1803-15 PMID: 11313928
  28. Chronic kidney disease: a European perspective.
    Kidney Int Suppl. 2005 Dec;(99):S30-8 PMID: 16336574
  29. Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney.
    Am J Transplant. 2005 Jun;5(6):1375-82 PMID: 15888044
  30. Mitogen activated protein kinases in renal fibrosis.
    Front Biosci (Schol Ed). 2009 Jun 01;1:171-87 PMID: 19482693
  31. Inducible nitric-oxide synthase is an important contributor to prolonged protective effects of ischemic preconditioning in the mouse kidney.
    J Biol Chem. 2003 Jul 18;278(29):27256-66 PMID: 12682064
  32. Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1.
    Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10660-5 PMID: 16818887
  33. Epithelial-mesenchymal transition and its implications for fibrosis.
    J Clin Invest. 2003 Dec;112(12):1776-84 PMID: 14679171
  34. TGF-beta signaling and the fibrotic response.
    FASEB J. 2004 May;18(7):816-27 PMID: 15117886
  35. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.
    Am J Pathol. 2010 Jan;176(1):85-97 PMID: 20008127
  36. Control of the G2/M transition.
    Mol Biotechnol. 2006 Mar;32(3):227-48 PMID: 16632889
  37. P53-Rb signaling pathway is involved in tubular cell senescence in renal ischemia/reperfusion injury.
    Biocell. 2007 Aug;31(2):213-23 PMID: 17902269
  38. Bone morphogenetic protein-7 and connective tissue growth factor: novel targets for treatment of renal fibrosis?
    Pharm Res. 2008 Oct;25(10):2416-26 PMID: 18266088
  39. Transforming growth factor-beta/connective tissue growth factor axis in the kidney.
    Int J Biochem Cell Biol. 2008;40(1):9-13 PMID: 17300978
  40. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation.
    Chromosoma. 1997 Nov;106(6):348-60 PMID: 9362543
  41. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury.
    J Am Soc Nephrol. 2009 Aug;20(8):1754-64 PMID: 19470675
  42. The role of ATM and ATR in DNA damage-induced cell cycle control.
    Prog Cell Cycle Res. 2003;5:393-411 PMID: 14593734
  43. Mechanism of action of taxol.
    Trends Pharmacol Sci. 1992 Apr;13(4):134-6 PMID: 1350385
  44. Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis.
    Am J Physiol Renal Physiol. 2005 Apr;288(4):F800-9 PMID: 15536170
  45. Role of the E2F1-p19-p53 pathway in ischemic acute renal failure.
    Nephron Physiol. 2005;101(2):p27-34 PMID: 15990448
  46. Cell cycle checkpoint signaling through the ATM and ATR kinases.
    Genes Dev. 2001 Sep 1;15(17):2177-96 PMID: 11544175
  47. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention.
    J Am Soc Nephrol. 2004 Jan;15(1):1-12 PMID: 14694152
  48. The role of tubular epithelial-mesenchymal transition in progressive kidney disease.
    Cells Tissues Organs. 2007;185(1-3):222-31 PMID: 17587828
  49. Cell cycle regulation: repair and regeneration in acute renal failure.
    Kidney Int. 2004 Aug;66(2):509-14 PMID: 15253699
  50. Acute kidney injury increases risk of ESRD among elderly.
    J Am Soc Nephrol. 2009 Jan;20(1):223-8 PMID: 19020007
  51. Renal recovery following acute kidney injury.
    Curr Opin Crit Care. 2008 Dec;14(6):660-5 PMID: 19005306
  52. Immunohistochemical and lectin dissection of the human nephron in health and disease.
    Arch Pathol Lab Med. 1993 Dec;117(12):1233-9 PMID: 8250694
Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2144
Published
2010-05-00
Epub
2010-00-02
Pages
535-43, 1p following 143
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC3928013
Subset
IM
Grants
NIDDK NIH HHS · DK074030 · United States
NIDDK NIH HHS · P50 DK074030 · United States
NIDDK NIH HHS · DK72381 · United States
NIDDK NIH HHS · R37 DK039773 · United States
NIDDK NIH HHS · F32 DK088418 · United States
NIDDK NIH HHS · R01 DK039773 · United States
NIDDK NIH HHS · R01 DK072381 · United States
NIDDK NIH HHS · DK39773 · United States
Corrections
CommentIn
PMID: 20448575
External Links
PubMed source DOI: 10.1038/nm.2144 PMC Full Text View journal details
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