title: Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion.
abstract: Aging of the male reproductive system leads to changes in endocrine signaling and is frequently associated with the emergence of prostate hyperplasia and bladder dysfunctions. Recent reports highlight prostate and bladder as promising targets for therapeutic interventions with inhibitors of the cyclic GMP (cGMP)-degrading phosphodiesterase 5 (PDE5). However, the cGMP signaling system in these organs is as yet poorly characterized, and the possibility of age-related alterations has not been addressed. This study investigates key proteins of cGMP pathways in bladder, prostate, and epididymis of young (3 months) and old (23-24 months) Wistar rats. Local differences in the abundance of PDE5, soluble guanylyl cyclase (sGC) and particulate guanylyl cyclases (GC-A, GC-B), endothelial nitric oxide synthase, and cGMP-dependent protein kinase I (PRKG1 (cGKI)) revealed pronounced tissue-specific peculiarities. Although cGMP-generating enzymes were not affected by age in all organs, we recognized age-related decreases of PDE5 expression in bladder and a selective diminishment of membrane-associated PRKG1 in epididymis. In disagreement with published data, all cGMP pathway proteins including PDE5 are poorly expressed in prostate. However, prostatic PRKG1 expression increases with aging. Androgen withdrawal during temporary Leydig cell elimination induced a massive (>12-fold) upregulation of PRKG1 in prostate but not in other (penis and epididymis) androgen-dependent organs. These findings identify PRKG1 as a key androgen-sensitive signaling protein in prostate of possible importance for growth regulation. The elucidated effects may have significance for age-associated pathologies in the male lower-urinary tract.
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Aulweg 123, 35385 Giessen, Germany. hans-dieter.mueller@anatomie.med.uni-giessen.de
authors.forename: Dieter
authors.initials: D
authors.lastname: Müller
authors.forename: Amal K
authors.initials: AK
authors.lastname: Mukhopadhyay
authors.forename: Michail S
authors.initials: MS
authors.lastname: Davidoff
authors.forename: Ralf
authors.initials: R
authors.lastname: Middendorff
mesh_terms: D000375:Aging / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism*; D007985:Leydig Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008698:Mesylates / Q000633:toxicity; D009928:Organ Specificity; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D015854:Up-Regulation; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000728:Androgens; D008698:Mesylates; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C002994:ethylene dimethanesulfonate; D006152:Cyclic GMP