Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model

Abstract

SUMMARYIndividuals 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 p27Kip1 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.

Hemicentin 1 influences podocyte dynamic changes in glomerular diseases

“…In this perspective, the identification of new genes suitable for the prediction and/or having a role in DN is of great importance (15). In recent years, different models of adipose tissue dysfunction have emerged as a valuable tool to study the renal disease in the context of metabolic syndrome/Type 2 diabetes (20,38,42). In our study, we found that the lipoatrophic Pparg ⌬/⌬ and the AZIP tg/ϩ mice are two excellent models for the study of DN at an early stage.…”

PPARγ and Its Agonists in Chronic Kidney Disease

“…Studies about animal models showed that PPARc-deficient mice presented lipid metabolic disorders. One earlier study using PPARc2 and leptin double knockout mice (POKO) showed that those mice presented spontaneous metabolic syndrome, hypertension, albuminuria, and renal dysfunction [72,73]. Another study showed that lipotoxicity accelerates lipid accumulation and inflammation and then leads to glomerular diseases, which suggested that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome [74].…”

Peroxisome Proliferator-Activated Receptor γ 2 Modulates Late-Pregnancy Homeostatic Metabolic Adaptations

“…Collectively, these data indicate that PPARγ2 is essential in promoting healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term. RNA extraction and quantitative RT-PCR were performed as reported (14,17). The input value of the gene of interest was standardized to a best housekeeper gene calculated using three different genes, 18S rRNA, b 2-microglobulin and b -actin mRNA, and the BestKeeper software tool (18).…”