Mechanism of Nephrotoxicity
Dickman and Sidorenko
In addition to being a urothelial carcinogen, aristolochic acid (AA) is a powerful and remarkably selective nephrotoxin, and we are actively seeking its mechanism of action. The chronic renal failure caused by AA is severe and irreversible, and patients with this disease often require dialysis therapy or a kidney transplant to survive. The kidney is the sole target organ of AA toxicity, and within the kidney, necrotic and apoptotic cell death occurs exclusively in the proximal tubule. This nephron segment is particularly prone to toxic injury due its important role in urinary elimination of drugs and other xenobiotics. Excretion some of these foreign compounds is mediated by a family of organic anion transport proteins localized to the proximal tubule. We have shown that these transporters have a remarkably high affinity for AA, in the sub-micromolar range, and concentrate the toxin inside proximal tubule cells, providing one basis for site-selective toxicity.
Having established how AA gains entry into its target cells, our research is now focused on identification of the molecular events that lead to proximal tubule cell death. At first glance, genomic DNA damage would appear to be an obvious mechanism of toxicity, and while this is surely the basis for the urothelial cancer caused by AA, it is not the proximate cause of kidney disease, as we have identified AA structural analogs that are genotoxic but not nephrotoxic. Currently, we are using a variety of custom-synthesized chemical tools, in combination with proteomics and genomics, to identify the genes, proteins and cellular pathways engaged in the initiation and progression of toxicity.
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