title: The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease.
abstract: OBJECTIVE
  We have recently shown increased sensitivity to IGF-I induced signal transduction in kidneys of diabetic mice. Accordingly we investigated the effects of PQ401, a novel diarylurea compound that inhibits IGF1R autophosphorylation in type I diabetes.
  
  
  METHODS
  Control (C) and Diabetic (D) mice were administered PQ401 (CP, DP) or vehicle (C, D) for 3weeks.
  
  
  RESULTS
  CP animals showed a decrease in renal phosphorylated (p-)AKT and p-IGF1R. However, PQ401 had no effect on diabetic state (hyperglycemia, weight loss) or renal disease parameters (hypertrophy, hyperfiltration and albuminuria). Type IV collagen as well as TGF-β mRNA increased in DP and D compared to C. In the CP group renal hypertrophy with fat accumulation in proximal tubuli and increased renal IGF-I, collagen IV and TGF-β mRNA were seen.
  
  
  CONCLUSIONS
  IGF1R inhibition by PQ401 exerted no significant effects on diabetic kidney disease parameters, arguing against a role for IGF-I in the pathogenesis of diabetic kidney disease. However, PQ401 affects normal kidneys, inducing renal hypertrophy as well as collagen and fat accumulation, with increased renal IGF-I mRNA, suggestive of a damage-regeneration process. Therefore, this diarylurea compound is not beneficial in early diabetic kidney disease. Its potential deleterious effects on kidney tissue need to be further investigated.
authors.affiliation: Shraga Segal Department of Microbiology and Immunology, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Troib
authors.forename: Daniel
authors.initials: D
authors.lastname: Landau
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
authors.forename: Leonid
authors.initials: L
authors.lastname: Kachko
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
authors.forename: Yael
authors.initials: Y
authors.lastname: Segev
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D024141:Collagen Type IV; C569479:PQ 401; D010671:Phenylurea Compounds; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1