Troib Ariel, Landau Daniel, Youngren Jack F, Kachko Leonid, Rabkin Ralph, Segev Yael
Shraga Segal Department of Microbiology and Immunology, Ben Gurion University of the Negev, Beer Sheva, Israel.
Growth Horm IGF Res. 2011 Oct;21(5):285-91. doi: 10.1016/j.ghir.2011.07.007. Epub 2011 Aug 23.
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.
Control (C) and Diabetic (D) mice were administered PQ401 (CP, DP) or vehicle (C, D) for 3weeks.
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.
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.
我们最近发现糖尿病小鼠肾脏对胰岛素样生长因子-I（IGF-I）诱导的信号转导敏感性增加。因此，我们研究了PQ401（一种新型二芳基脲化合物）对I型糖尿病中IGF1R自磷酸化的抑制作用。
给对照（C）小鼠和糖尿病（D）小鼠施用PQ401（CP、DP）或赋形剂（C、D），持续3周。
CP组动物肾脏磷酸化（p-）AKT和p-IGF1R水平降低。然而，PQ401对糖尿病状态（高血糖、体重减轻）或肾脏疾病参数（肥大、超滤和蛋白尿）没有影响。与C组相比，DP组和D组IV型胶原蛋白以及TGF-β mRNA水平升高。在CP组中，可见近端小管脂肪堆积导致的肾脏肥大以及肾脏IGF-I、胶原蛋白IV和TGF-β mRNA水平升高。
PQ401对IGF1R的抑制作用对糖尿病肾病参数没有显著影响，这表明IGF-I在糖尿病肾病发病机制中不起作用。然而，PQ401会影响正常肾脏，导致肾脏肥大以及胶原蛋白和脂肪堆积，同时肾脏IGF-I mRNA水平升高，提示存在损伤-再生过程。因此，这种二芳基脲化合物对早期糖尿病肾病无益。其对肾脏组织的潜在有害作用需要进一步研究。
