The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease

Ariel Troib, Daniel Landau, Jack F. Youngren, Leonid Kachko, Ralph Rabkin, Yael Segev*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 3. weeks. 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.

Original languageEnglish
Pages (from-to)285-291
Number of pages7
JournalGrowth Hormone and IGF Research
Volume21
Issue number5
DOIs
StatePublished - Oct 2011
Externally publishedYes

Keywords

  • Diabetic nephropathy
  • Diarylurea
  • IGF-I
  • IGF1 receptor
  • Nephrotoxicity
  • Non-obese diabetic mice

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