TY - JOUR
T1 - The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease
AU - Troib, Ariel
AU - Landau, Daniel
AU - Youngren, Jack F.
AU - Kachko, Leonid
AU - Rabkin, Ralph
AU - Segev, Yael
N1 - Funding Information: This study was supported by a Grant-in-aid of the US-Israel Binational Science Foundation (no. 2003055 ) to DL, RR, and YS, and a National Institute of Health Grant RO1 DK 068517 and a Merit Review Grant from the Research Service of the US Department Veterans Affairs to RR.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
KW - Diabetic nephropathy
KW - Diarylurea
KW - IGF-I
KW - IGF1 receptor
KW - Nephrotoxicity
KW - Non-obese diabetic mice
UR - http://www.scopus.com/inward/record.url?scp=80052596471&partnerID=8YFLogxK
U2 - 10.1016/j.ghir.2011.07.007
DO - 10.1016/j.ghir.2011.07.007
M3 - Article
C2 - 21865067
SN - 1096-6374
VL - 21
SP - 285
EP - 291
JO - Growth Hormone and IGF Research
JF - Growth Hormone and IGF Research
IS - 5
ER -
