Tubular Cells to Chemically Induced Injury.
Toxicol Appl Pharmacol. 2009 Aug 11. [Epub ahead of print]
Zhong Q, Terlecky SR, Lash LH.
Department of Pharmacology, Wayne State University School of Medicine,
Detroit, MI 48201.
Diabetic nephropathy is characterized by increased oxidative stress and
mitochondrial dysfunction. In the present study, we prepared primary
cultures of proximal tubular (PT) cells from diabetic rats 30 days after an
ip injection of streptozotocin and compared their susceptibility to oxidants
(tert-butyl hydroperoxide, methyl vinyl ketone) and a mitochondrial toxicant
(antimycin A) with that of PT cells isolated from age-matched control rats,
to test the hypothesis that PT cells from diabetic rats exhibit more
cellular and mitochondrial injury than those from control rats when exposed
to these toxicants. PT cells from diabetic rats exhibited higher basal
levels of reactive oxygen species (ROS) and higher mitochondrial membrane
potential, demonstrating that the PT cells maintain the diabetic phenotype
in primary culture. Incubation with either the oxidants or mitochondrial
toxicant resulted in greater necrotic and apoptotic cell death, greater
evidence of morphological damage, greater increases in ROS, and greater
decreases in mitochondrial membrane potential in PT cells from diabetic rats
than in those from control rats. Pretreatment with either the antioxidant
N-acetyl-L-cysteine or a catalase mimetic provided equivalent protection of
PT cells from both diabetic and control rats. Despite the greater
susceptibility to oxidative and mitochondrial injury, both cytoplasmic and
mitochondrial glutathione concentrations were markedly higher in PT cells
from diabetic rats, suggesting an upregulation of antioxidant processes in
diabetic kidney. These results support the hypothesis that primary cultures
of PT cells from diabetic rats are a valid model in which to study renal
cellular function in the diabetic state.
PMID: 19682476 [PubMed - as supplied by publisher]
