title: Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.
abstract: 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 (PPARγ2) 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 β-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 (TGFβ) 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.
authors: Universidad Rey Juan Carlos, Dpto. de Bioquímica, Fisiología y Genética Molecular, Avda. de Atenas s/n. 28922, Alcorcón, Madrid, Spain.
authors: Cristina
authors: C
authors: Martínez-García
authors: Adriana
authors: A
authors: Izquierdo
authors: Vidya
authors: V
authors: Velagapudi
authors: Yurena
authors: Y
authors: Vivas
authors: Ismael
authors: I
authors: Velasco
authors: Mark
authors: M
authors: Campbell
authors: Keith
authors: K
authors: Burling
authors: Fernando
authors: F
authors: Cava
authors: Manuel
authors: M
authors: Ros
authors: Matej
authors: M
authors: Oresic
authors: Antonio
authors: A
authors: Vidal-Puig
authors: Gema
authors: G
authors: Medina-Gomez
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D005838:Genotype; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D006984:Hypertrophy; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007333:Insulin Resistance; D007674:Kidney Diseases / Q000150:complications* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000633:toxicity*; D024821:Metabolic Syndrome / Q000150:complications* / Q000473:pathology*; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002518:Ceramides; D004075:Diglycerides; D016326:Extracellular Matrix Proteins; D008055:Lipids; D047495:PPAR gamma; D014280:Triglycerides; D005947:Glucose