PMID- 22773754
OWN - NLM
STAT- MEDLINE
DCOM- 20130107
LR  - 20240214
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Print)
IS  - 1754-8403 (Linking)
VI  - 5
IP  - 5
DP  - 2012 Sep
TI  - Accelerated renal disease is associated with the development of metabolic 
      syndrome in a glucolipotoxic mouse model.
PG  - 636-48
LID - 10.1242/dmm.009266 [doi]
AB  - Individuals with metabolic syndrome are at high risk of developing chronic kidney 
      disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are 
      known to induce glucolipotoxic effects in metabolically relevant organs. However, 
      the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy 
      is debated. We generated a murine model, the POKO mouse, obtained by crossing the 
      peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) knockout (KO) mouse 
      into a genetically obese ob/ob background. We have previously shown that the POKO 
      mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as 
      early as 4 weeks of age, and developed a complete loss of normal beta-cell function 
      by 16 weeks of age. Metabolic phenotyping of the POKO model has led to 
      investigation of the structural and functional changes in the kidney and changes 
      in blood pressure in these mice. Here we demonstrate that the POKO mouse is a 
      model of renal disease that is accelerated by high levels of glucose and lipid 
      accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an 
      increased urinary albumin:creatinine ratio and significantly increased blood 
      pressure, but in contrast showed a significant increase in the renal hypertrophy 
      index and an associated increase in p27(Kip1) expression compared with their 
      obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin 
      resistance, an alteration of lipid metabolism and glomeruli damage associated 
      with increased transforming growth factor beta (TGFbeta) and parathyroid 
      hormone-related protein (PTHrP) expression. At this age, levels of 
      proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), 
      and fibrotic factors were also increased at the glomerular level compared with 
      levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. 
      These data suggest an accelerated lesion through glucolipotoxic effects in the 
      renal pathogenesis in POKO mice.
FAU - Martinez-Garcia, Cristina
AU  - Martinez-Garcia C
AD  - Universidad Rey Juan Carlos, Dpto. de Bioquimica, Fisiologia y Genetica 
      Molecular, Avda. de Atenas s/n. 28922, Alcorcon, Madrid, Spain.
FAU - Izquierdo, Adriana
AU  - Izquierdo A
FAU - Velagapudi, Vidya
AU  - Velagapudi V
FAU - Vivas, Yurena
AU  - Vivas Y
FAU - Velasco, Ismael
AU  - Velasco I
FAU - Campbell, Mark
AU  - Campbell M
FAU - Burling, Keith
AU  - Burling K
FAU - Cava, Fernando
AU  - Cava F
FAU - Ros, Manuel
AU  - Ros M
FAU - Oresic, Matej
AU  - Oresic M
FAU - Vidal-Puig, Antonio
AU  - Vidal-Puig A
FAU - Medina-Gomez, Gema
AU  - Medina-Gomez G
LA  - eng
GR  - G0600717/MRC_/Medical Research Council/United Kingdom
GR  - G0802051/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120705
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
RN  - 0 (Biomarkers)
RN  - 0 (Ceramides)
RN  - 0 (Diglycerides)
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Lipids)
RN  - 0 (PPAR gamma)
RN  - 0 (Triglycerides)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Aging/drug effects/pathology
MH  - Animals
MH  - Biomarkers/metabolism
MH  - Ceramides/metabolism
MH  - Diglycerides/metabolism
MH  - Disease Models, Animal
MH  - *Disease Progression
MH  - Extracellular Matrix Proteins/metabolism
MH  - Fibrosis
MH  - Genotype
MH  - Glucose/metabolism/*toxicity
MH  - Hypertrophy
MH  - Inflammation/complications/pathology
MH  - Insulin Resistance
MH  - Kidney Diseases/*complications/*pathology
MH  - Kidney Glomerulus/drug effects/pathology/ultrastructure
MH  - Lipid Metabolism/drug effects
MH  - Lipids/*toxicity
MH  - Metabolic Syndrome/*complications/*pathology
MH  - Metabolomics
MH  - Mice
MH  - Mice, Knockout
MH  - PPAR gamma/metabolism
MH  - Triglycerides/metabolism
PMC - PMC3424461
EDAT- 2012/07/10 06:00
MHDA- 2013/01/08 06:00
PMCR- 2012/09/01
CRDT- 2012/07/10 06:00
PHST- 2012/07/10 06:00 [entrez]
PHST- 2012/07/10 06:00 [pubmed]
PHST- 2013/01/08 06:00 [medline]
PHST- 2012/09/01 00:00 [pmc-release]
AID - dmm.009266 [pii]
AID - 0050636 [pii]
AID - 10.1242/dmm.009266 [doi]
PST - ppublish
SO  - Dis Model Mech. 2012 Sep;5(5):636-48. doi: 10.1242/dmm.009266. Epub 2012 Jul 5.