Abstract
Metabolic syndrome can induce chronic kidney disease in humans. Genetically engineered mice on a C57BL/6 background are highly used for mechanistic studies. Although it has been shown that metabolic syndrome induces cardiovascular lesions in C57BL/6 mice, in depth renal phenotyping has never been performed. Therefore in this study we characterized renal function and injury in C57BL/6 mice with long-term metabolic syndrome induced by a high fat and fructose diet (HFFD). C57BL/6 mice received an 8 months HFFD diet enriched with fat (45% energy from fat) and drinking water enriched with fructose (30%). Body weight, food/water consumption, energy intake, fat/lean mass ratio, plasma glucose, HDL, LDL, triglycerides and cholesterol levels were monitored. At 3, 6 and 8 months, renal function was determined by inulin clearance and measure of albuminuria. At sacrifice, kidneys and liver were collected. Metabolic syndrome in C57BL/6 mice fed a HFFD was observed as early 4 weeks with development of type 2 diabetes at 8 weeks after initiation of diet. However, detailed analysis of kidney structure and function showed only minimal renal injury after 8 months of HFFD. HFFD induced moderate glomerular hyperfiltration (436,4 µL/min vs 289,8 µL/min; p-value=0.0418) together with a 2-fold increase in albuminuria only after 8 months of HFFD. This was accompanied by a 2-fold increase in renal inflammation (p-value=0.0217) but without renal fibrosis or mesangial matrix expansion. In addition, electron microscopy did not show alterations in glomeruli such as basal membrane thickening and foot process effacement. Finally, comparison of the urinary peptidome of these mice with the urinary peptidome from humans with diabetic nephropathy also suggested absence of diabetic nephropathy in this model. This study provides evidence that the HFFD C57BL/6 model is not the optimal model to study the effects of metabolic syndrome on the development of diabetic kidney disease.
Highlights
The food industry has evolved, providing a supply of increasingly rich diet in terms of fatty acids [1] and fructose [2]
Histological analysis of the liver performed at 8 months revealed a marked vacuolar degeneration, indicating fat accumulation in the liver (Figure 3). This observation is consistent with the development of non alcoholic fatty liver (NAFLD) due to the excess of fructose intake [46]. These data strongly suggest the presence of metabolic syndrome as early as 4 weeks and of associated type 2 diabetes (T2D) as early as 8 weeks after initiation of a high fat and fructose diet (HFFD) in C57BL/6 mice
For comparison with the human situation we studied the regulation of the 273 peptides associated to chronic kidney diseases (CKD) in healthy controls (n=33, data obtained from [40]), in patients with T2D without diabetic nephropathy and in patients with T2D with diabetic nephropathy that were previously studied by Molin [50]
Summary
The food industry has evolved, providing a supply of increasingly rich diet in terms of fatty acids [1] and fructose [2]. This shift is not without consequences on general health including increase risk of developing obesity, insulin resistance, hepatic steatosis and diabetes [3,4,5,6,7,8,9,10]. It has been shown that metabolic syndrome is associated with a higher prevalence of microalbuminuria [15,16,17,18,19,20] and an higher risk of development of CKD [21] and subsequent end stage renal disease (ESRD) in type II diabetic patients [22]. Detailed mechanistic information on the link between metabolic syndrome and CKD is not available
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