Evidence that age-related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats.
The current studies were initiated to investigate whether excessive oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogen-activated protein kinase (MAPK) signaling pathways. Western blot analysis indicated that aging caused increased phosphorylation and activation of rat adrenal p38 MAPK, but not the ERK1/2 or JNK1/2. Lipid peroxidation measurements (an index of cellular oxidative stress) indicated that adrenal membranes from young animals contained only minimal levels of endogenous thiobarbituric acid-reactive substances (TBARS), and exposure of membranes to enzymatic and non-enzymatic pro-oxidants enhanced TBARS formation approximately 12- and 20-fold, respectively. The adrenal membranes from old animals showed much more susceptibility to lipid peroxidation and exhibited roughly 4- to 6-fold higher TBARS formation than young controls both under basal conditions and in response to pro-oxidants. Qualitatively similar results were obtained when lipid peroxide formation was measured using a sensitive FOXRS (ferrous oxidation-xylenol orange-reactive substances) technique. We next tested whether aging-induced excessive oxidative insult alters steroidogenesis through modulation of MAPK signaling pathway. Treatment of adrenocortical cells from old rats with specific p38 MAPK inhibitors restored Bt(2)cAMP-stimulated steroidogenesis approximately 60-70% of the value seen in cells of young animals. Likewise, pretreatment of cells with reactive oxygen species (ROS) scavengers MnTMPyP and N-acetyl cysteine also partially rescued age-induced loss of steroid production. In contrast, simultaneous treatment of cells with ROS scavengers and p38 MAPK inhibitor did not produce any additional effect suggesting that both types of inhibitors exert their stimulatory action through inhibition of p38 MAPK activation. Collectively, these results indicate that p38 MAPK functions as a signaling effector in oxidative stress-induced inhibition of steroidogenesis during aging.
Abidi
Parveen
P
Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Leers-Sucheta
Susan
S
Cortez
Yuan
Y
Han
Jiahuai
J
Azhar
Salman
S
D000302:Adrenal Cortex / Q000201:enzymology; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis / Q000172:deficiency*; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016166:Free Radical Scavengers; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015227:Lipid Peroxidation; D020935:MAP Kinase Signaling System; D008297:Male; D008665:Metalloporphyrins; D016877:Oxidants; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000305:Adrenal Cortex Hormones; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D016877:Oxidants; D017392:Thiobarbituric Acid Reactive Substances; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases