Toxic nephropathy: Environmental chemicals

The kidney is the target of numerous xenobiotic toxicants, including environmental chemicals. Anatomical, physiological, and biochemical features of the kidney make it particularly sensitive to many environmental compounds. Factors contributing to the sensitivity of the kidney include: large blood flow, the presence of a variety of xenobiotic transporters and metabolizing enzymes, and concentration of solutes during urine production. In many cases, the conjugation of environmental chemicals to glutathione and/or cysteine targets these chemicals to the kidney where inhibition of renal function occurs through a variety of mechanisms. For example, heavy metals such as mercury and cadmium target the kidney after glutathione/cysteine conjugation. Trichloroethlene and bromobenzene are metabolized and conjugated to glutathione in the liver before renal uptake and toxicity. In contrast, renal injury produced by chloroform and aristolochic acids is dependent on renal cytochrome P450 metabolism to toxic metabolites. Other compounds, such as paraquat or diquat, damage the kidney via the production of reactive oxygen species. Finally, the low solubility of ethylene glycol metabolites causes crystal formation within the tubular lumen and nephrotoxicity. This chapter explores mechanisms of nephrotoxicity by environmental chemicals, using these example compounds. What remains to be accomplished and by far the most difficult process is the elucidation of the detailed mechanisms of tubular cell injury after toxicant uptake and metabolism. The large number of individuals experiencing a decline in renal function with age makes the search for these mechanisms very compelling

Extracellular signal-regulated kinase activation mediates mitochondrial dysfunction and necrosis induced by hydrogen peroxide in renal proximal tubular cells

Although tubular necrosis in acute renal failure is associated with excessive production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), the mechanism of ROS-induced cell necrosis remains poorly understood. In this study, we examined the role of the extracellular signaling-regulated kinase (ERK) pathway in H2O2-induced necrosis of renal proximal tubular cells (RPTC) in primary culture. Exposure of 60 to 70% confluent RPTC to 1 mM H2O2 for 3 h resulted in 44% necrotic cell death, as measured by trypan blue uptake, and inactivation of mitogen-activated protein kinase kinase (MEK), the upstream activator of ERK, by either 1,4-diamino-2,3-dicyano-1,4- bis[2-aminophenylthio] butadiene (U0126) or 2-(2 '-amino- 3 '-methoxyphenyl)-oxanaphthalen-4-one (PD98059) or overexpression of dominant-negative mutant of MEK1, inhibited cell death. In contrast, overexpression of active MEK1 enhanced H2O2-induced cell death. H2O2 treatment led to the loss of mitochondrial membrane potential (MMP) in RPTC, which was decreased by U0126 and PD98059. Furthermore, inhibition of the MEK/ERK pathway decreased oxidant-mediated ERK1/2 activation and mitochondrial swelling in isolated renal cortex mitochondria. However, treatment with cyclosporin A (CsA), a mitochondrial permeability transition blocker, did not suppress RPTC necrotic cell death, loss of MMP, and mitochondrial swelling. We suggest that ERK is a critical mediator of mitochondrial dysfunction and necrotic cell death of renal epithelial cells following oxidant injury. Oxidant-induced necrotic cell death was mediated by a CsA-insensitive loss of MMP that is regulated by the ERK pathway