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Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model
Universidad Rey Juan Carlos, Dpto. de Bioquímica, Fisiología y Genética Molecular, Madrid, Spain.
Universidad Rey Juan Carlos, Dpto. de Bioquímica, Fisiología y Genética Molecular, Madrid, Spain.
VTT Technical Research Centre of Finland, Espoo, Finland.
Universidad Rey Juan Carlos, Dpto. de Bioquímica, Fisiología y Genética Molecular, Madrid, Spain.
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2012 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 5, no 5, p. 636-48Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
The Company of Biologists , 2012. Vol. 5, no 5, p. 636-48
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-63671DOI: 10.1242/dmm.009266ISI: 000308737400013PubMedID: 22773754Scopus ID: 2-s2.0-84865496736OAI: oai:DiVA.org:oru-63671DiVA, id: diva2:1169234
Note

Funding Agencies:

Ramon y Cajal programme from Ministerio de Ciencia e Innovacion (MICINN) BFU2009-10006 BFU2008-04901-C03-03 

Universidad Rey Juan Carlos-Comunidad de Madrid CCG10-URJC/BIO-560 

Comunidad de Madrid S2010/BMD-2423 

L'Oreal "Women for Science"  

FP6 Hepadip, Diabetes UK  

MRC programme grant  MRC CORD 

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-01-23Bibliographically approved

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