PMID- 23940580
OWN - NLM
STAT- MEDLINE
DCOM- 20140305
LR  - 20220321
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 8
DP  - 2013
TI  - Increased cellular senescence and vascular rarefaction exacerbate the progression 
      of kidney fibrosis in aged mice following transient ischemic injury.
PG  - e70464
LID - 10.1371/journal.pone.0070464 [doi]
LID - e70464
AB  - Recent findings indicate that elderly patients with acute kidney injury (AKI) 
      have an increased incidence of progression to chronic kidney disease (CKD) due to 
      incomplete recovery from an acute insult. In the current study, a co-morbid model 
      of AKI was developed to better mimic the patient population and to investigate 
      whether age exacerbates the fibrosis and inflammation that develop in the 
      sequelae of progressive kidney disease following acute injury. Young (8-10 weeks) 
      and aged (46-49 weeks) C57BL/6 mice were subjected to 30 min bilateral renal 
      ischemia-reperfusion (I/R) to induce AKI. The aged animals have greater mortality 
      and prolonged elevation of plasma creatinine correlating with less tubular 
      epithelial cell proliferation compared to the young. Six weeks post-reperfusion, 
      interstitial fibrosis is greater in aged kidneys based on picrosirius red 
      staining and immunolocalization of cellular fibronectin, collagen III and 
      collagen IV. Aged kidneys 6 weeks post-reperfusion also express higher levels of 
      p53 and p21 compared to the young, correlating with greater increases in 
      senescence associated (SA) beta-galactosidase, a known marker of cellular 
      senescence. A higher influx of F4/80(+) macrophages and CD4(+) T lymphocytes is 
      measured and is accompanied by increases in mRNA of monocyte chemoattractant 
      protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha). Importantly, microvascular 
      density is significantly less, correlating with an increase in nitro-tyrosine, a 
      marker of oxidative stress. Collectively, these data demonstrate that prolonged 
      acute injury in the aged animals results in an accelerated progression of kidney 
      disease in a chronic state.
FAU - Clements, Meghan E
AU  - Clements ME
AD  - Tissue Protection and Repair Unit, Genzyme R&D, Genzyme, a division of Sanofi, 
      Framingham, Massachusetts, USA.
FAU - Chaber, Christopher J
AU  - Chaber CJ
FAU - Ledbetter, Steven R
AU  - Ledbetter SR
FAU - Zuk, Anna
AU  - Zuk A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130805
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Chemokine CCL2)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Acute Kidney Injury/metabolism/*pathology
MH  - Animals
MH  - Cellular Senescence/*physiology
MH  - Chemokine CCL2/metabolism
MH  - Fibrosis/metabolism/*pathology
MH  - Kidney/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Reperfusion Injury/metabolism/*pathology
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC3734312
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts: All authors are employees of Genzyme, a Sanofi company. The 
      authors do not have any other relevant declarations relating to patents, products 
      in development, or marketed products. This does not alter the authors' adherence 
      to all the PLOS ONE policies on sharing data and materials.
EDAT- 2013/08/14 06:00
MHDA- 2014/03/07 06:00
PMCR- 2013/08/05
CRDT- 2013/08/14 06:00
PHST- 2012/12/07 00:00 [received]
PHST- 2013/06/24 00:00 [accepted]
PHST- 2013/08/14 06:00 [entrez]
PHST- 2013/08/14 06:00 [pubmed]
PHST- 2014/03/07 06:00 [medline]
PHST- 2013/08/05 00:00 [pmc-release]
AID - PONE-D-12-38766 [pii]
AID - 10.1371/journal.pone.0070464 [doi]
PST - epublish
SO  - PLoS One. 2013 Aug 5;8(8):e70464. doi: 10.1371/journal.pone.0070464. Print 2013.