Angiotensin II-induced mesangial cell apoptosis: role of oxidative stress.
BACKGROUND
Angiotensin II (ANG II) has been shown to play a role in the induction of glomerular injury. In the present study, we evaluated the effects of ANG II on mesangial cell apoptosis and the involved molecular mechanism.


METHODS
The effect of ANG II on apoptosis of mouse mesangial cells (MC) was evaluated by morphologic, DNA fragmentation and TUNEL assays. To evaluate the role of oxidative stress and involved mechanisms, we studied the effect of antioxidants, anti-TGF-beta antibody, inhibitors of nitric oxide synthase and modulators of cytosolic calcium/heme oxygenase (HO) activity. In addition, we studied the effect of ANG II on the generation of reactive oxygen species (ROS) by MCs.


RESULTS
ANG II promoted apoptosis of MCs in a dose dependent manner. This effect of ANG II was not only associated with ROS production, but also inhibited by antioxidants. Both Anti-TGF-beta antibody and propranolol inhibited ANG II-induced ROS generation and apoptosis. BAPTA inhibited both ANG II- and TGF-beta-induced apoptosis. On the other hand, thapsigargin stimulated MC apoptosis under basal as well as ANG II/TGF-beta stimulated states. ANG II receptor types 1 and 2 antagonists attenuated the proapoptotic effect of ANG II. Hemin inhibited but zinc protoporphyrin enhanced the proapoptotic effect of ANG II. Propranolol increased HO activity; whereas pre-treatment with propranolol prevented ANG II-induced apoptosis.


CONCLUSIONS
ANG II promotes MC apoptosis. This effect of ANG II is mediated through downstream signaling involving TGF-beta, phospholipase D, and Ca(2+), contributing to the activation of NADPH oxidase and generation of ROS. HO activity plays a modulatory role in ANG II- induced MC apoptosis.
Lodha
Saurabh
S
Immunology and Inflammation Center for Excellence, North Shore-Long Island Jewish Research Institute, Manhasset, USA.
Dani
Dhimant
D
Mehta
Rajeev
R
Bhaskaran
Madhu
M
Reddy
Krishna
K
Ding
Guohua
G
Singhal
Pravin C
PC
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D005920:Glomerular Mesangium / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000378:metabolism
D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019255:NADPH Oxidases