Abstract
The major site of fructose metabolism in the kidney is the proximal tubule (PT). To test whether insulin and/or IGF1 signaling in the PT is involved in renal structural/functional responses to dietary fructose, we bred mice with dual knockout (KO) of the insulin receptor (IR) and the IGF1 receptor (IGF1R) in PT by Cre‐lox recombination, using a γ‐glutamyl transferase promoter. KO mice had slightly (~10%) reduced body and kidney weights, as well as, a reduction in mean protein‐to‐DNA ratio in kidney cortex suggesting smaller cell size. Under control diet, IR and IGF1R protein band densities were 30–50% (P < 0.05) lower than WT, and the relative difference was greater in male animals. Male, but not female KO, also had significantly reduced band densities for Akt (protein kinase B), phosphorylated AktT308 and IRY 1162/1163. A high‐fructose diet (1‐month) led to a significant increase in kidney weight in WT males (12%), but not in KO males or in either genotype of female mice. Kidney enlargement in the WT males was accompanied by a small, insignificant fall in protein‐to‐DNA ratio, supporting hyperplasia rather than hypertrophy. Fructose feeding of male WT mice led to significantly higher sodium bicarbonate exchanger (NBCe1), sodium hydrogen exchanger (NHE3), sodium phosphate co‐transporter (NaPi‐2), and transforming growth factor‐β (TGF‐β) abundances, as compared to male KO, suggesting elevated transport capacity and an early feature of fibrosis may have accompanied the renal enlargement. Overall, IR and/or IGF1R appear to have a role in PT cell size and enlargement in response to high‐fructose diet.
Highlights
Metabolic syndrome (MetS) is a common and escalating constellation of clinically associated disorders including dyslipidemia, insulin resistance, visceral adiposity, and hypertension (Isomaa 2003)
Mice with dual knockout (KO) of the insulin receptor (IR) and IGF1 receptor (IGF1R) selectively from the proximal tubule were generated at Georgetown University by crossing mice that were homozygously floxed for both genes, with mice carrying Cre-recombinase driven by the c-glutamyltransferase promoter
Overall staining was less intense for both IR and IGF1R in proximal tubule in KO mice
Summary
Metabolic syndrome (MetS) is a common and escalating constellation of clinically associated disorders including dyslipidemia, insulin resistance, visceral adiposity, and hypertension (Isomaa 2003). Poor diet and increasing rates of obesity are at the root of MetS. Fructose has remarkably alternative whole-body metabolism, as compared to glucose, and due to its less rate-limited metabolism, its rapid conversion to triglycerides can be associated with cellular ATP depletion and high circulating levels of uric acid (Johnson et al 2013). It has been estimated that 60–70% of reabsorbed fructose is taken up by the liver, and undergoes metabolism at this site (Johnson et al 2010). Another 30–40% appears to be metabolized by kidney, adipose tissue, and other organs
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