Effect of iron on renal tubular epithelial cells

Abstract

Since iron has been implicated as a potential nephrotoxin, we examined the effect of iron on several aspects of cultured renal tubular epithelial cell biology. We found that exposure to 10(-4) M of either the ferrous or ferric form of iron impaired healing of denuded areas made within confluent monolayers of LLC-PK1 cells. This impairment required 30 to 80 hours of exposure to iron to occur and was also seen in another renal tubular epithelial cell line (MDCK cells). To delineate the potential mechanism(s) of this impairment, we examined the expression of a key integrin subunit involved in cell-matrix adhesion. Exposure of LLC-PK1 cells to 10(-4) M ferric citrate for 72 hours significantly decreased expression of the beta 1 integrin subunit as determined by flow cytometry. To determine if iron impairs another process that occurs at the basolateral surface, the effects of 72 hours of exposure to iron on adenylate cyclase activity were examined. Both ferric and ferrous citrate significantly enhanced vasopressin- and forskolin-stimulated adenylate cyclase activity. To examine if iron can regulate proliferation, the effect of iron on 3H-thymidine uptake was measured. We found that ferric citrate diminished proliferation and this decrease required the presence of either serum or transferrin. To ascertain if iron affected ultrastructure, we used transmission electron microscopy and found that iron accumulation within cells was much more apparent with ferric than ferrous citrate. Ferric iron induced mild-to-moderate cytopathic changes. These results indicate that iron is capable of inducing multiple changes in renal tubular epithelial function. The effect of iron to impair wound healing may be related to diminished expression of the beta 1 integrin subunit and perhaps to impaired proliferation.

Plasma Catalytic Iron, AKI, and Death among Critically Ill Patients

“…By catalyzing the Haber-Weiss and Fenton reactions, catalytic iron combines with superoxide to ultimately form the very reactive and injurious hydroxyl radical (2,24). In the kidney, iron impairs proliferation of renal tubular epithelial cells via dysregulation of cell-matrix adhesion (25). In animal models of AKI, catalytic iron levels are elevated in the All iron markers are natural log-transformed, given their skewed distribution, and standardized to 1 SD to allow comparison across biomarkers.…”

Novel Biomarkers, Oxidative Stress, and the Role of Labile Iron Toxicity in Cardiopulmonary Bypass-Associated Acute Kidney Injury

“…Ischemia-reperfusion injury during CPB may further exacerbate oxidoinflammatory stress in the setting of free circulating labile iron. Free labile iron is capable of inducing multiple changes in renal tubular epithelial function, including impaired proliferation (67) and the induction of free radical injuries, such as lipid peroxidation and protein oxidation. The generation of hydroxyl radicals is catalyzed by free iron ions and most active at acid pH (Fig.…”

No Nitric Oxide for HO-1 from Sodium Nitroprusside

“…Although they acknowledge that iron is known to be involved in the regulation of genes and pro- teins, particularly those with pro-or anti-inflammatory functions, no attempt is made to explain the stimulatory effect of iron on the adenylyl cyclase/cAMP system. However, considerable evidence has accumulated over the past few decades that free iron can increase adenylyl cyclase activity, either alone or in synergy with other stimuli (Baba et al, 1981;Tan et al, 1995;Sponsel et al, 1996). The underlying signaling mechanisms apparently involve the formation of reactive oxygen species (ROS) via iron-catalyzed free radical formation (Fenton reaction).…”