Absence of renal enlargement in fructose-fed proximal-tubule-select insulin receptor (IR), insulin-like-growth factor receptor (IGF1R) double knockout mice

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.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

“…The variability of protein isoforms of the insulin signalling cascade (IRecs, IRS, PI3K, and AKT) [122] and of diabetes phenotypes, mainly in T2D [182,183], is partially due to genetic variations [184][185][186] and may be related to specific tissue resistance differences. In addition, insulin signalling determines several phenotypic characteristics regarding cell size and proliferation in PTs [187]. Therefore, another question is if the insulin action on PT glucose transport is impaired in insulin resistance.…”

Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice

“…Characterization of the knockout Some aspects of the Insr/Igf1r PT-select double KO mouse have been previously described [22]. Fig.…”

“…Mice with targeted dual knockout (KO) of the insulin receptor (Insr) and IGF1 receptor (Igf1r) from the proximal tubule (PT) were generated at Georgetown University by crossing mice that were homozygously floxed for both genes with mice carrying Cre-recombinase driven by the γ-glutamyltransferase (γGT) promoter [22]. Mice were housed in conventional cages with 12-hour light/dark cycles.…”

Proximal and Distal Nephron-specific Adaptation to Furosemide

“…These data have implications for kidney repair in the setting of acute or chronic injury when tubular proliferation may be warranted 85,86 . Moreover, targeting the IGF-1R to minimize potentially unwanted hypertrophy in the setting of diuretic resistance or other hypertrophic stimuli 87 , would not limit distal tubular hypertrophy. Differential expression at one week demonstrate specificity for changes in genes for IGF binding proteins 51 , Igfbp1 and Igfbp5 in proximal, but not distal tubular cell types.…”

“…These data have implications for kidney repair in the setting of acute or chronic injury when tubular proliferation may be warranted 85,86 . Moreover, targeting the IGF-1R to minimize potentially unwanted hypertrophy in the setting of diuretic resistance or other hypertrophic stimuli 87 24,88 . Alternatively, the full-length form of IGFBP-5 can reduce IGF-1 bioavailability, and therefore IGF-1R-mediated signaling [89][90][91][92] .…”