title: 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 AktT308and IRY1162/1163A 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.
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia.
authors.forename: Lijun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia.
authors.forename: Marcus
authors.initials: M
authors.lastname: Byrd
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia.
authors.forename: Kwame
authors.initials: K
authors.lastname: Doh
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia.
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Dixon
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia.
authors.forename: Hwal
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia.|Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Swasti
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia ecelbarc@georgetown.edu.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Ecelbarger
mesh_terms: D000818:Animals; D004032:Diet; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D027982:Sodium-Bicarbonate Symporters; D017923:Sodium-Hydrogen Exchangers; D050608:Sodium-Phosphate Cotransporter Proteins; D016212:Transforming Growth Factor beta; D005632:Fructose; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: Insulin resistance; metabolic syndrome; renal enlargement; renal tubular acidosis; sex differences