High-Fructose Diet Increases Renal ChREBPβ Expression, Leading to Intrarenal Fat Accumulation in a Rat Model with Metabolic Syndrome.

Abstract

Simple SummaryFructose consumption leads to the development of metabolic syndrome. Fatty liver and chronic kidney disease are closely related to metabolic syndrome. Lately, a transcription factor that regulates fructose metabolism in the liver, named ChREBPβ, which is responsible for de-novo lipogenesis and intra-hepatic fat accumulation (“fatty liver”), was described. In this study, we demonstrate that the effect of fructose consumption on the kidneys resembles its liver effect. Rats fed with a high-fructose diet exhibit bigger kidneys with higher triglycerides content, compared to control rats. The expression of ChREBPβ and its downstream genes was upregulated as well. Treating kidney-origin cells with fructose increased the expression of this factor as well, showing the direct effect of fructose on this factor. Thus, the appearance of fatty kidney in response to high-fructose consumption revealed a new mechanism linking metabolic syndrome to chronic kidney disease.Fructose consumption is associated with metabolic syndrome (MeS). Dysregulated lipid metabolism and ectopic lipid accumulation, such as in “fatty liver’’, are pivotal components of the syndrome. MeS is also associated with chronic kidney disease (CKD). The aim of this study was to evaluate kidney fructose metabolism and whether the addition of fructose leads to intrarenal fat accumulation. Sprague Dawley rats were fed either normal chow (Ctrl) or a high-fructose diet (HFrD). MeS features such as blood pressure and metabolic parameters in blood were measured. The kidneys were harvested for ChREBPβ and de novo lipogenesis (DNL) gene expression, triglyceride content and histopathology staining. HK2 (human kidney) cells were treated with fructose for 48 h and gene expression for ChREBPβ and DNL were determined. The HFrD rats exhibited higher blood pressure, glucose and triglyceride levels. The kidney weight of the HFrD rats was significantly higher than Ctrl rats. The difference can be explained by the higher triglyceride content in the HFrD kidneys. Oil red staining revealed lipid droplet formation in the HFrD kidneys, which was also supported by increased adipophilin mRNA expression. For ChREBPβ and its downstream genes, scd and fasn, mRNA expression was elevated in the HFrD kidneys. Treating HK2 cells with 40 mM fructose increased the expression of ChREBPβ. This study demonstrates that fructose consumption leads to intrarenal lipid accumulation and to the formation of a “fatty kidney”. This suggests a potential mechanism that can at least partially explain CKD development in fructose-induced MeS.