Published online before print March 5, 2009

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(American Journal of Pathology. 2009;174:1191-1202.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080654

Alterations in Fatty Acid Utilization and an Impaired Antioxidant Defense Mechanism Are Early Events in Podocyte Injury

A Proteomic Analysis

Corina Mayrhofer^*, Sigurd Krieger^*, Nicole Huttary^*, Martina Wei-Fen Chang, Johannes Grillari, Günter Allmaier and Dontscho Kerjaschki^*

From the Clinical Institute of Pathology,^* Medical University of Vienna, Vienna; the Institute of Chemical Technologies and Analytics, Vienna University of Technology, Vienna; the Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Vienna; and BMT Research Vienna, Vienna, Austria

Ultrastructural alterations of podocytes are closely associated with loss of glomerular filtration function. In the present study, we explored changes at the proteome level that paralleled the disturbances of podocyte architecture in the early stages of puromycin aminonucleoside (PA) nephrosis in vivo. Using two-dimensional fluorescence difference gel electrophoresis and vacuum matrix-assisted laser desorption/ionization mass spectrometry combined with postsource decay fragment ion analysis and high- energy collision-induced dissociation tandem mass spectrometry, 23 differentially expressed protein spots, corresponding to 16 glomerular proteins that are involved in various cellular functions, were unambiguously identified, and a subset was corroborated by Western blot analysis. The majority of these proteins were primarily related to fatty acid metabolism and redox regulation. Key enzymes of the mitochondrial β-oxidation pathway and antioxidant enzymes were consistently down-regulated in PA nephrosis. These changes were paralleled by increased expression levels of CD36. PA treatment of murine podocytes in culture resembled these specific protein changes in vitro. In this cell system, the modulatory effects of albumin-bound fatty acids on the expression levels of Mn-superoxide dismutase in response to PA were demonstrated as well. Taken together, these results indicate that a disrupted fatty acid metabolism in concert with an impaired antioxidant defense mechanism in podocytes may play a role in the early stages of PA-induced lesions in podocytes.