Insulin-Like Growth Factor-I Is an Important Antiapoptotic Factor for Rat Leydig Cells during Postnatal Development

• Published in: Endocrinology (Philadelphia) Vol. 148; no. 1; pp. 128 - 139
• Main Authors: Colón, Eugenia, Zaman, Farasat, Axelson, Magnus, Larsson, Olle, Carlsson-Skwirut, Christine, Svechnikov, Konstantin V, Söder, Olle
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-01-2007; Oxford University Press
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Androstadienes - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bcl-2 protein; Biological and medical sciences; Caspase-3; Cell activation; Cell survival; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Developmental stages; DNA - biosynthesis; DNA nucleotidylexotransferase; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Growth factors; IAP protein; Immunohistochemistry; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factor I receptors; Insulin-like growth factor II; Insulin-Like Growth Factor II - pharmacology; Insulin-like growth factors; Kinases; Leydig cells; Leydig Cells - cytology; Leydig Cells - metabolism; Male; Medicin och hälsovetenskap; Phosphorylation; Phosphorylation - drug effects; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - pharmacology; Postpartum period; Protein Kinase Inhibitors - pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Steroidogenic acute regulatory protein; Survival; Testis - cytology; Testis - growth & development; Testis - physiology; Vertebrates: endocrinology; Western blotting; Vertebrata; Mammalia; Rat; Animal; Rodentia; Testicle; Insulin like growth factor 1; Male genital system; Postnatal development; Leydig cell
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-0835

The present investigation examines the influence of IGF-I and the role of IGF-I receptor (IGF-IR) in the apoptosis/survival of Leydig cells. Immunohistochemical analysis of the rat testis at different ages revealed that the level of the phosphorylated IGF-IR increases from birth to d 20 of postnatal life, remaining high in the adult testis. Western blotting revealed that this level is higher in Leydig cells isolated from 40-d-old than from 10- or 60-d-old rats. Application of the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay revealed that IGF-I decreases the level of apoptosis in Leydig cells at all stages of development, and the selective inhibitor of IGF-IR, picropodophyllin, blocks this antiapoptotic effect. The mechanism underlying the antiapoptotic action of IGF-I involves the phosphatidylinositol 3-kinase/Akt pathway, and in immature Leydig cells, this growth factor enhances the expression of Bcl-2 and cellular inhibitor of apoptosis proteins 2, while preventing activation of caspase-3 by cleavage. Furthermore, IGF-II and high concentrations of insulin also evoke phosphorylation of IGF-IR and, like IGF-I, enhance the expression of the steroidogenic acute regulatory protein by Leydig cells. Inhibition of IGF-IR by picropodophyllin decreases the survival of Leydig cells, both in the presence and absence of IGF-I, demonstrating that signaling via the IGF-IR plays an important role in Leydig cell survival.