Abstract
The molecular mechanism of the aging-associated dysfunction of Leydig cells (LCs) is complex and poorly understood. In this study, we analyzed the contribution of nitric oxide (NO) and cGMP signaling to the age-dependent decline in LC function. Significant (>50%) decreases in serum, intratesticular, and LC androgens in aging rats (15-24 months) were accompanied by a proportional increase in NO production, an up-regulation of cGMP levels, and the expression of soluble guanylyl cyclase-1B and protein kinase G1 in LCs. In contrast, LC cAMP levels decreased with age, most likely reflecting the up-regulation of cAMP-specific phosphodiesterase expression. Moreover, the expression of genes encoding enzymes responsible for cholesterol transport and its conversion to T were reduced. Exposing LCs from aged animals to NO further increased cGMP levels and decreased cAMP and androgen production, whereas the addition of cell-permeable 8-bromoguanosine-cGMP alone had the opposite effect. In vivo inhibition of cGMP-specific phosphodiesterase-5 for 3 and 6 months in aged rats led to a partial restoration of androgens, NO, and cyclic nucleotide levels, as well as the expression of steroidogenic and NO/cGMP signaling genes. These results indicate that a progressive increase in NO production contributes to the age-dependent decrease in steroidogenesis in a cGMP-independent manner, whereas the sustained elevation in cGMP levels significantly slows the decline in LC function.
Publication types
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Comparative Study
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging*
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Androgens / blood
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Androgens / metabolism*
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Animals
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Cells, Cultured
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Cyclic AMP / metabolism*
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Cyclic GMP-Dependent Protein Kinase Type I / biosynthesis
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Cyclic GMP-Dependent Protein Kinase Type I / genetics
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Cyclic GMP-Dependent Protein Kinase Type I / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 5 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
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Fertility Agents, Male / pharmacology
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Gene Expression Regulation, Developmental / drug effects
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Guanylate Cyclase / biosynthesis
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Guanylate Cyclase / genetics
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Guanylate Cyclase / metabolism
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Leydig Cells / cytology
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Leydig Cells / drug effects
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Leydig Cells / metabolism*
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Male
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Nitric Oxide / metabolism*
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Phosphodiesterase 5 Inhibitors / pharmacology
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Second Messenger Systems* / drug effects
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Soluble Guanylyl Cyclase
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Testis / cytology
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Testis / drug effects
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Testis / growth & development
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Testis / metabolism*
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Up-Regulation
Substances
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Androgens
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Fertility Agents, Male
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Phosphodiesterase 5 Inhibitors
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Receptors, Cytoplasmic and Nuclear
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Nitric Oxide
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Cyclic AMP
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Cyclic GMP-Dependent Protein Kinase Type I
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Prkg1 protein, rat
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Pde5a protein, mouse
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Guanylate Cyclase
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Soluble Guanylyl Cyclase