In vivo imaging of advanced glycation end products (AGEs) of albumin: first observations of significantly reduced clearance and liver deposition properties in mice

Abstract

Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.

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“…Additionally, they also demonstrated 14 C labelled product in the lungs and spleen which were not examined in the present study. Very recently, an in vivo study using a similar near infrared label for whole murine trafficking by IVIS following intravenous injection in BALB/c nu-nu mice was published [264]. Similar to our findings they saw significant accumulation in the liver of AGE modified Human Serum Albumin (AGE-HSA) compared to unmodified HSA [264], persisting in the liver for 24 hours after injection.…”

“…Only very small quantities of the near IR-AGE-HSA were detected in the kidneys, pancreas and brain, that were negligible compared to the quantities detected in the liver [264]. By contrast, IR-AGE-BSA was not detected in the liver beyond the 15 minutes in the present study.…”

“…As discussed in chapter 2, this was contrary to the findings of other groups [255,262,369,374]. However, our findings do align with those from other researchers using similar AGE modified proteins [249,264] and to long term feeding studies with isotopically labelled AGEs [263]. Possible explanations for these discrepancies were discussed at length in chapter 2, but are likely the result of variation in the type of AGE modified protein used, the sensitivity of the detection system and differences between AGEs administered orally vs intravenously.…”

“…Although the pancreas showed no detectable AGEs after this single delivery, significant accumulation of IR-AGE and IR-BSA was detected in the liver by 15 minutes. Both acute trafficking studies [249,264] and long term feeding studies [263] suggest the liver is an important site of AGE sequestration and clearance in rodents. This is not surprising, given the liver receives greater than 70% of its blood supply from the GI tract [388].…”

“…Given this was a pilot and technically laborious, only three mice per group, per time-point were used in experiment 2 and all mice were male. Therefore, it was not statistically powered to make rigorous quantitative comparisons or to assess sex differences in uptake and [262,264]. Therefore, small sample sizes have been typically used for trafficking and uptake studies.…”