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

Abstract

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.

Keywords: ChREBPβ; fatty kidney; fructose; metabolic syndrome.

Figure 1

High-fructose diet (HFrD)-fed rats developed hypertension and increased blood triglycerides and glucose level. Blood pressure (BP) was measured using tail cuff (a). Blood triglycerides and glucose were measured at the end of the experiment (b,c). * p ≤ 0.05. n = 7–8.

Figure 2

HFrD increased kidney weight and induced ectopic lipid accumulation in the kidneys. Kidney weight was measured at the end of the study and was normalized to body weight (a). Total kidney triglycerides were measured using a colorimetric Assay Kit (b). Ectopic lipid accumulation was measured by oil red O staining in the renal cortex, representative slides, and 20× magnification (c). Kidney adipophilin expression levels were measured by real time PCR (d). * p ≤ 0.05. n = 7–8.

Figure 3

Fructose consumption increased ChREBPβ and its downstream genes RNA expression. HFrD increased the expression of genes in the kidney that regulate de novo lipogenesis (a–g), gluconeogenesis (h–j) and fructose intake and metabolism (k–m). Gene expression was measured by real time PCR. * p ≤ 0.05. n = 7–8.

Figure 4

Fructose but not glucose upregulates ChREBPβ expression in the human kidney cell line HK2. HK2 cells have been treated with fructose (a) or glucose (b), at 10, 20 and 40 mM, and ChREBPβ expression level, were measured. Fructose-treated cells were also screened for the DNL ChREBPβ downstream genes—Fasn (c), Acc (d), Scd (e), Elovl6 (f) and adipophilin (g). * p ≤ 0.05. The results represent 4–8 experiments.