An alternative hypothesis on the role of chemically induced protein droplet (α2u-globulin) nephropathy in renal carcinogenesis

Abstract

Based on associations between the accumulation of protein droplets containing α2u-globulin in proximal tubular epithelial cells and increased incidences of renal tubular neoplasms in male rats, it has been suggested that the carcinogenicity of chemicals that cause α2u-globulin nephropathy is unique to animals that synthesize this protein. Chemicals that caused α2u-globulin nephropathy and renal carcinogenicity in male rats have not been shown to produce renal tumors in animals that lack the capability for hepatic α2u-globulin systhesis, including female rats, male NBR rats, or mice of either sex. Because humans do not synthesize α2u-globulin it has been suggested that chemicals which cause renal toxicity associated with α2u-globulin accumulation do not pose an increased cancer risk to humans. In this review on the association between α2u-globulin nephropathy and renal carcinogenesis, it is apparent that (a) there are data inconsistent with the hypothesis linking these occurrences, (b) alternative mechanisms of renal toxicity and carcinogenicity are plausible, (c) data on quantitative dose-response correspondences between the various stages of α2u-globulin nephropathy and renal carcinogenicity are limited, and (d) a greater understanding of the molecular changes occurring during renal carcinogenesis is needed before assuming that the current hypothesis is correct. Future research aimed at resolving issues raised in this paper should help determine whether or not the association between α2u-globulin nephropathy and renal carcinogenesis represents a cause-and-effect relationship.