389-P: ChREBP-ß Aggravates Fructose-Induced Renal Tubular Reabsorption Disorder by Regulating Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is essential for fructose metabolism in mice. Renal fructose metabolism occurs mainly in the renal tubules. As a constitutively active form, ChREBP-β is expressed at extremely low levels. To date, the functional significance of ChREBP-β in renal fructose metabolism remains unclear. Here, we show that ChREBP-β regulates fructose-induced renal tubular reabsorption disorder by controlling endoplasmic reticulum stress and mitochondrial respiration. Kidney ChREBP-β mRNA levels were elevated upon fructose exposure, which prompted us to generate a mouse model overexpressing ChREBP-β specifically in renal tubules. ChREBP-β overexpression led to renal tubular reabsorption disorder, as evidenced by increased markers NAG and β2-MG and rupture of the brush border of the renal tubule. Mechanistically, ChREBP-β overexpression upregulated the expression of genes like ATF4 involved in endoplasmic reticulum stress and downregulated those involved in mitochondrial respiration. Furthermore, apoptosis gene expression was markedly activated in the kidney by ChREBP-β overexpression. Taken together, our work establishes a critical role of kidney ChREBP-β in coping with renal tubular reabsorption disorder.