Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress.
Aldosterone has attracted significant consideration for its role in the progression of renal injury. Since apoptotic cell loss contributes to the deterioration of renal function, we examined the effect of aldosterone on tubular cell apoptosis. To determine dose and time course effect, human renal proximal tubular (HK2) cells were treated with aldosterone at different doses and for variable time periods followed by evaluation for apoptosis. To determine the role of mineralocorticoid receptors (MR) and oxidative stress, HK2 cells were treated with either vehicle or aldosterone in the presence or absence of spironolactone/antioxidants/free radical scavengers (FRS) followed by evaluation for apoptosis. The presence of MR was evaluated using RT-PCR. Reactive oxygen species (ROS) generation was evaluated using redox-sensitive dyes. Effect of aldosterone was evaluated on dephosphorylation of phospho-Bad and accumulation of cytosolic cytochrome c. Human tubular cells express MR. Aldosterone promotes tubular cell apoptosis in a dose- and time-dependent manner. This effect of aldosterone is mediated through MR and associated with generation of ROS. Antioxidants and FRS partially attenuated the proapoaptotic effect of aldosterone. Aldosterone enhanced dephosphorylation of phospho-Bad and accumulation of cytosolic cytochrome c. We conclude that aldosterone-induced tubular cell apoptosis is mediated through the activation of the mitochondrial pathway and generation of ROS.
Patni
Hitesh
H
Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, New Hyde Park, NY 11042, USA.
Mathew
Jayant T
JT
Luan
Liming
L
Franki
Nicholas
N
Chander
Praveen N
PN
Singhal
Pravin C
PC
D000450:Aldosterone / Q000502:physiology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D045304:Cytochromes c