Abstract
Obesity-related albuminuria is associated with decline of kidney function and is considered a first sign of diabetic nephropathy. Suggested factors linking obesity to kidney dysfunction include low-grade inflammation, insulin resistance and adipokine dysregulation. Here, we investigated the effects of two pharmacological compounds with established anti-inflammatory properties, rosiglitazone and rosuvastatin, on kidney dysfunction during high-fat diet (HFD)-induced obesity. For this, human CRP transgenic mice were fed standard chow, a lard-based HFD, HFD+rosuvastatin or HFD+rosiglitazone for 42 weeks to study effects on insulin resistance; plasma inflammatory markers and adipokines; and renal pathology. Rosiglitazone but not rosuvastatin prevented HFD-induced albuminuria and renal fibrosis and inflammation. Also, rosiglitazone prevented HFD-induced KIM-1 expression, while levels were doubled with rosuvastatin. This was mirrored by miR-21 expression, which plays a role in fibrosis and is associated with renal dysfunction. Plasma insulin did not correlate with albuminuria. Only rosiglitazone increased circulating adiponectin concentrations. In all, HFD-induced albuminuria, and renal inflammation, injury and fibrosis is prevented by rosiglitazone but not by rosuvastatin. These beneficial effects of rosiglitazone are linked to lowered miR-21 expression but not connected with the selectively enhanced plasma adiponectin levels observed in rosiglitazone-treated animals.
Highlights
Obesity rates are rapidly rising worldwide in almost all populations and age groups, largely due to increased availability and consumption of calorie-dense foods with a high-fat, high-sugar content and lack of physical activity[1]
The three experimental groups that received high-fat diet (HFD) all showed a gradual increase in body weight over time and all had significantly higher average body weights at the end of the experimental period (t = 42 weeks) compared with the group that remained on chow (35.1 ± 1.9 g)
All mice fed HFD showed a clear increase in fat mass compared with chow-fed mice, but what was most striking were the observed differences in fat mass distribution over the various fat depots in the different groups (Fig. 1a–c)
Summary
Obesity rates are rapidly rising worldwide in almost all populations and age groups, largely due to increased availability and consumption of calorie-dense foods with a high-fat, high-sugar content and lack of physical activity[1]. Reduce systemic inflammation and insulin are attractive candidates for preventive treatment of patients at risk for developing (diabetic) nephropathy Another explanation for renal disease in obesity may be related to the notion that adipocytes are an active endocrine cell type[8, 9]. To gain more insight into the role of inflammation and adiponectin in metabolic-stress-induced albuminuria, renal inflammation and fibrosis in the context of IR, we used a human CRP transgenic (huCRPtg) mouse model. The huCRPtg mouse carries a transgene containing the human CRP gene, the 5′ flanking promoter region and all known human CRP gene regulatory elements[13] These mice have been successfully employed to monitor systemic inflammation and to determine the effects and mechanisms of drugs like statins and fibrates in reducing inflammatory process[14]. An integral part of the study was to assess a putative role of adiponectin, which is induced by rosiglitazone
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