Regional protein alterations in rat kidneys induced by lead exposure

Lead is a potent neuro- and nephrotoxin in humans and a renal carcinogen in rats. Previous studies have detected lead-induced increases in the activit ies of specific detoxification enzymes in distinct kidney cell types preced ing irreversible renal damage. While preferential susceptibility of the hig hly vascularized cortex to the effects of lead is clear, lead effects on th e medullary region have remained unexplored. The present study was undertak en to investigate the extent to which regional renal protein expression dif fers and to determine which, if any, regionally distinct protein markers in dicative of lead's renotoxic mechanism might be detected in kidney cortical and medullary cytosols. We examined protein expression in these two functi onally and anatomically distinct regions, and identified several proteins t hat are differentially expressed in those regions and were significantly al tered by lead. Kidney cytosols from rats injected with lead acetate (114 mg /kg, three consecutive daily injections) were separated by two-dimensional electrophoresis. Lead exposure significantly (P<0.001) altered the abundanc e (either up arrow or down arrow) of 76 proteins in the cortex and only 13 in the medulla. Eleven of the proteins altered in the protein patterns were conclusively identified either by matrix-assisted laser desorption/ionizat ion mass spectrometry / electrospray ionization-mass spectrometry (MALDI-MS /ESI-MS) analysis of peptide digests, immunological methods, or by gel matc hing. Several of the cortical proteins altered by lead were unchanged in th e medulla while others underwent similar but lesser alterations. These obse rvations reflect the complexity of lead's nephrotoxicity and endorse the ap plication of proteomics in mechanistic studies as well as biomarker develop ment in a variety of toxicologic paradigms.