Hypertensive nephrosclerosis: not enough of a good thing?

GLUTATHIONE S-TRANSFERASES (GSTs) are multifunctional enzymes that are perhaps best known to participate in cell detoxification by catalyzing the conjugation of reduced glutathione to a wide variety of xenobiotics that have electrophilic centers. Production of these adducts promotes cytoprotection and further increases their subsequent cellular excretion (10). As understanding of these enzymes has broadened, it is now apparent that GSTs participate in S-glutathionylation reactions involved in a wide range of cellular functions that include the regeneration of S-thiolated proteins and catalysis in metabolic pathways not associated with detoxification (11). GSTs critically contribute to the cellular defense against reactive oxygen species (ROS) (11). As a consequence of existing in an oxygen-rich environment, intracellular ROS, as well as reactive nitrogen species, are constantly produced. Their presence shifts the intracellular balance between oxidation and reduction; the subsequent changes in redox homeostasis alter cell function. GSTs are integrally involved in the metabolism of these reactive compounds and oxidized products. For example, GSTs catalyze the glutathionylation of peroxidized lipid products such as the toxic electrophile 4-hydroxynonenal (4-HNE) (9). GSTs also regulate signal transduction events activated by ROS and mediated through the JNK pathway (11). GSTs are regulated in part by nuclear factor-erythroid 2-related factor 2 (Nrf2), which stimulates transcription by binding to the cis-acting antioxidant response element (ARE) present in the promoter regions of GSTs (12). Thus GSTs are an integral component of the cellular antioxidant network that is regulated by the redox-sensitive transcription factor Nrf2, which is highly expressed in the kidney. GSTs comprise a multigene collection of enzymes with complex phylogeny, but they may be divided into four different families: cytoplasmic, microsomal, mitochondrial, and bacterial. These four GST protein families contain members that are evolutionarily related yet may have very different functions. Human cytosolic GST isozymes are dimeric and can be subdivided into seven classes that share sequence homology: Alpha, Mu, Omega, Pi, Theta, Sigma, and Zeta. Five different human Mu-class subunits (GSTM1–5) have been identified (8). The complexity and seeming redundancy of this large enzyme family might suggest that alteration in just one of these enzymes would not be sufficient to modify cellular or organ function, but such may not be the case. GST polymorphisms have been associated with reduced protective capacity and accelerated progression in diseases associated with oxidative stress (4). Several lines of evidence suggest that GSTs participate integrally in vascular biology and function. GSTM1(0), the GSTM1 null allele, is associated with a more rapid increase in common carotid intima media thickness in smokers (2). Reductions in GSTM1 levels in vascular smooth muscle cells (VSMC) in vitro result in the production of ROS and cellular proliferation (14). Rats subjected to acute hypotension demonstrate upregulation of GSTM1 in the kidney, potentially leading to an increased degradation of ROS (13). Reductions in Address for reprint requests and other correspondence: P. W. Sanders, Div. of Nephrology/Dept. of Medicine, 642 Lyons-Harrison Research Bldg. 1530 Third Ave., South, Univ. of Alabama at Birmingham, Birmingham, AL 35294-0007 (e-mail: [email protected]).