Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity

Abstract

Renal toxicity is a hallmark of uranium exposure, with uranium accumulating specifically in the S3 segment of the proximal tubules causing tubular damage. As the distribution, concentration and dynamics of accumulated uranium at the cellular level is not well understood, here, we report on high-resolution quantitative in situ measurements by high-energy synchrotron radiation X-ray fluorescence analysis in renal sections from a rat model of uranium-induced acute renal toxicity. One day after subcutaneous administration of uranium acetate to male Wistar rats at a dose of 0.5 mg uranium kg(-1) body weight, uranium concentration in the S3 segment of the proximal tubules was 64.9 ± 18.2 µg g(-1) , sevenfold higher than the mean renal uranium concentration (9.7 ± 2.4 µg g(-1) ). Uranium distributed into the epithelium of the S3 segment of the proximal tubules and highly concentrated uranium (50-fold above mean renal concentration) in micro-regions was found near the nuclei. These uranium levels were maintained up to 8 days post-administration, despite more rapid reductions in mean renal concentration. Two weeks after uranium administration, damaged areas were filled with regenerating tubules and morphological signs of tissue recovery, but areas of high uranium concentration (100-fold above mean renal concentration) were still found in the epithelium of regenerating tubules. These data indicate that site-specific accumulation of uranium in micro-regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney.

Intracellular uranium distribution: Comparison of cryogenic fixation versus chemical fixation methods for SIMS analysis

“…In addition, we have previously shown from in vivo experiments i using SIMS microscopy that uranium is heterogeneously distributed in the nephron and localized mainly in cell nuclei of proximal convoluted tubules (Poisson et al, ; Tessier et al, ). Similar uranium distribution has been observed using different imaging technic in case of acute renal contamination in rats (Homma‐Takeda et al, ). The lower resolution of particle induced X‐ray emission (PIXE) images in this study, compared to the SIMS microscopy did not allowed observing n heterogeneous subcellular distribution of uranium.…”

“…It has been previously shown by us and others that at level below 1 µg/g of kidney for in vivo experiments and below 100 µM for in vitro experiments, close to realistic exposure levels, uranium did not induced direct deleterious toxic effects but induced biological pathways related to cell and tissue defense (Guéguen et al, ; Leggett et al, 1989; Prat et al, ). Recent in vivo experimental studies have confirmed that uranium distribution is highly heterogeneous within the kidney and can reach concentration tenfold higher than the mean renal tissue level (Homma‐Takeda et al, ).…”

A novel calibration strategy based on internal standard–spiked gelatine for quantitative bio-imaging by LA-ICP-MS: application to renal localization and quantification of uranium

“…The precise location and accurate quantification of uranium in rodents' kidneys would facilitate trustworthy information for reconstructing a more realistic dosimetry model for a better estimation of health risk that could be related to renal dysfunction or cancer occurrence in workers exposed to uranium. To date, few quantitative studies have been carried out employing high-energy synchrotron radiation X-ray fluorescence (SR-XRF) analysis and X-ray absorption fine structure (XAFS) [16,17]. Unfortunately, the limited access to these analytical techniques limits considerably its daily use for routine analysis [18].…”

Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity

“…DU is a heavy metal and can emit α and β particles; thus, it exhibits both heavy metal toxicity and radiotoxicity. The kidney is the major target organ of acute DU exposure, and DU can cause severe necrosis of renal proximal tubule endothelial cells, ultimately leading to acute renal failure or even death345. The following mechanisms of action underlie the nephrotoxicity of DU6: (1) altering ion transport in cells to inhibit the oxidative phosphorylation of mitochondria and utilization of adenosine triphosphate (ATP); (2) altering the expression of certain genes (associated with inflammation, oxidative stress, and homeostasis); and (3) increasing oxidative stress levels and decreasing anti-oxidation in cells, thus increasing DNA damage and promoting apoptosis.…”