Delayed apoptosis post-cadmium injury in renal proximal tubule epithelial cells.
BACKGROUND
Accumulation of the widespread environmental toxin cadmium (Cd) in the kidney results initially in proximal tubule dysfunction. Exposure to Cd has been previously shown to induce apoptosis in LLC-PK (Lily Laboratory Culture, Porcine Kidney) cells, which are a model of proximal tubule epithelium.


OBJECTIVE
We postulated that modulation of the components of the apoptotic pathway triggered by Cd is amenable to therapeutic intervention.


METHODS
We subjected confluent LLC-PK cells grown on two-compartment filters and on plastic to Cd (1-50 microM). Apoptosis and changes in components of the apoptotic pathway were measured by immunocytochemical and immunoblot analysis during the period of exposure and following Cd withdrawal.


RESULTS
Insignificant apoptosis was seen during exposure to Cd and immediately after removal of this metal. Two waves of apoptosis were noted 6 and 48 h after the Cd was removed from the apical compartment. The apoptosis 48 h post-Cd exposure was accompanied by a decrease in cellular ATP levels and transepithelial resistance and preceded by an increase in p38 phosphorylation. Inhibition of p38 mitogen-activated protein kinase activity decreased the delayed apoptotic peak, without affecting the rate of recovery of the integrity of the renal epithelium. IGF-1 neither altered the delayed apoptosis nor facilitated the rate of recovery of the integrity of the renal epithelium.


CONCLUSIONS
We demonstrate that following exposure to Cd, renal epithelial cells undergo significant apoptosis, which appears to involve p38 and is not amenable to IGF therapy.
Stinson
Lindsay J
LJ
Department of Pharmacology and Toxicology, University of Western Ontario, Child Health Research Institute, London, Ont, Canada.
Darmon
Alison J
AJ
Dagnino
Lina
L
D'Souza
S J A
SJ
D000818:Animals; D017209:Apoptosis; D002104:Cadmium / Q000633:toxicity*; D007687:Kidney Tubules, Proximal; D013552:Swine
D002104:Cadmium