Impact of hypoxia on IGF-I, IGF-II, IGFBP-3, ALS and IGFBP-1 regulation and on IGF1R gene expression in children

Hypoxia is one of many factors involved in the regulation of the IGF system. However, no information is available regarding the regulation of the IGF system by acute hypoxia in humans. Objective: The aim of this study was to evaluate the effect of acute hypoxia on the IGF system of children. Design: Twenty-seven previously health children (14 boys and 13 girls) aged 15 days to 9.5 years were studied in two different situations: during a hypoxemic state (HS) due to acute respiratory distress and after full recovery to a normoxemic state (NS). In these two situations oxygen saturation was assessed with a pulse-oximeter and blood samples were collected for serum IGF-I, IGF-II, IGFBP-1, IGFBP-3, ALS and insulin determination by ELISA; fluoroimmunometric assay determination for GH and also for IGF1R gene expression analysis in peripheral lymphocytes by quantitative real-time PCR. Data were paired and analyzed by the Wilcoxon non-parametric test. Results: Oxygen saturation was significantly lower during HS than in NS (P<0.0001). IGF-I and IGF-II levels were lower during HS than in NS (P<0.0001 and P=0.0004. respectively). IGFBP-3 levels were also lower in HS than in NS (P=0.0002) while ALS and basal GH levels were higher during HS (P=0.0015 and P=0.014, respectively). Moreover, IGFBP-1 levels were higher during HS than in NS (P=0.004). No difference was found regarding insulin levels. The expression of IGF1R mRNA as 2(-Delta Delta CT) was higher during HS than in NS (P=0.03). Conclusion: The above results confirm a role of hypoxia in the regulation of the IGF system also in humans. This effect could be direct on the liver and/or mediated by GH and it is not restricted to the hepatocytes but involves other cell lines. During acute hypoxia a combination of alterations usually associated with reduced IGF action was observed. The higher expression of IGF1R mRNA may reflect an up-regulation of the transcriptional process. (C) 2012 Elsevier Ltd. All rights reserved.

Adipose Tissue-Derived Stem Cell Treatment Prevents Renal Disease Progression

Adipose tissue-derived stem cells (ASCs) are an attractive source of stem cells with regenerative properties that are similar to those of bone marrow stem cells. Here, we analyze the role of ASCs in reducing the progression of kidney fibrosis. Progressive renal fibrosis was achieved by unilateral clamping of the renal pedicle in mice for 1 h; after that, the kidney was reperfused immediately. Four hours after the surgery, 2 x 10(5) ASCs were intraperitoneally administered, and mice were followed for 24 h posttreatment and then at some other time interval for the next 6 weeks. Also, animals were treated with 2 x 10(5) ASCs at 6 weeks after reperfusion and sacrificed 4 weeks later to study their effect when interstitial fibrosis is already present. At 24 h after reperfusion, ASC-treated animals showed reduced renal dysfunction and enhanced regenerative tubular processes. Renal mRNA expression of IL-6 and TNF was decreased in ASC-treated animals, whereas IL-4. IL-10, and HO-1 expression increased despite a lack of ASCs in the kidneys as determined by SRY analysis. As expected, untreated kidneys shrank at 6 weeks, whereas the kidneys of ASC-treated animals remained normal in size, showed less collagen deposition, and decreased staining for FSP-1, type I collagen, and Hypoxyprobe. The renal protection seen in ASC-treated animals was followed by reduced serum levels of TNF-alpha, KC, RANTES, and IL-1 alpha. Surprisingly, treatment with ASCs at 6 weeks, when animals already showed installed fibrosis, demonstrated amelioration of functional parameters, with less tissue fibrosis observed and reduced mRNA expression of type I collagen and vimentin. ASC therapy can improve functional parameters and reduce progression of renal fibrosis at early and later times after injury, mostly due to early modulation of the inflammatory response and to less hypoxia, thereby reducing the epithelial-mesenchymal transition.