Potential of an Interorgan Network Mediated by Toxic Advanced Glycation End-Products in a Rat Model

Abstract

Excessive intake of glucose and fructose in beverages and foods containing high-fructose corn syrup (HFCS) plays a significant role in the progression of lifestyle-related diseases (LSRD). Glyceraldehyde-derived advanced glycation end-products (AGEs), which have been designated as toxic AGEs (TAGE), are involved in LSRD progression. Understanding of the mechanisms underlying the effects of TAGE on gene expression in the kidneys remains limited. In this study, DNA microarray analysis and quantitative real-time polymerase chain reaction (PCR) were used to investigate whether HFCS-consuming Wister rats generated increased intracellular serum TAGE levels, as well as the potential role of TAGE in liver and kidney dysfunction. HFCS consumption resulted in significant accumulation of TAGE in the serum and liver of rats, and induced changes in gene expression in the kidneys without TAGE accumulation or upregulation of receptor for AGEs (RAGE) upregulation. Changes in specific gene expression profiles in the kidney were more correlated with TAGE levels in the liver tissue than in the serum. These findings suggest a direct or indirect interaction may be present between the liver and kidneys that does not involve serum TAGE or RAGE. The involvement of internal signal transduction factors such as exosomes or cytokines without IL-1β and TNF-α is suggested to contribute to the observed changes in kidney gene expression.

Keywords: high-fructose corn syrup (HFCS); intracellular TAGE; kidney; lifestyle-related diseases (LSRD); microarray; serum levels of TAGE; toxic advanced glycation end-products (TAGE).

Figure 1

Representative images of hematoxylin and eosin-stained Wistar rat kidney (A) and liver (B) tissues from the high-fructose corn syrup (HFCS) and control groups. The scale bar represents 50 µm.

Figure 2

Quantitative analysis of serum toxic advanced glycation end product (TAGE) levels (A) and intracellular TAGE levels in the liver (B) in the high-fructose corn syrup (HFCS) and control groups of rats. Data are presented as the mean ± standard deviation (n = 10). * p < 0.05 HFCS versus control group (Mann-Whitney U-test).

Figure 3

Analysis of high-fructose corn syrup (HFCS)-induced genes in the kidneys. (A) Volcano plot of HFCS-induced genes in the kidney, detected by DNA microarray analysis in the HFCS versus control group. The red dots indicate high gene expression levels, while the blue dots indicate low gene expression levels. (fold change >1.5; p < 0.05 by t-test). (B) Ingenuity pathway analysis-identified HFCS-induced gene network.

Figure 4

mRNA expression of Cyp24a, Plin2, Usp2, and Calb1 genes in Wistar rat kidneys from the high-fructose corn syrup (HFCS) and control groups. Expression levels of the target genes were normalized to those of β-actin (n = 10 per group). * p < 0.05 HFCS versus control group (Mann-Whitney U-test). RQ, relative quantification by real-time polymerase chain reaction.

Figure 5

Relationships between serum toxic advanced glycation end-products (TAGE) concentrations and expression levels of Cyp24a (A), Plin2 (B), Usp2 (C), and Calb1 (D) in Wistar rat kidneys. RQ, relative quantification by real-time polymerase chain reaction (n = 10 per group).

Figure 6

Relationships between intracellular toxic advanced glycation end-products (TAGE) levels in the liver of Wistar rats and expression of Cyp24a (A), Plin2 (B), Usp2 (C), and Calb1 (D) in the kidneys. RQ, relative quantification by real-time polymerase chain reaction (n = 10 per group).