title: Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome.
abstract: In the male, metabolic syndrome (MetS) is associated to an increased risk of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). A recently established rabbit model of high fat diet (HFD)-induced MetS showed hypogonadism and the presence of prostate gland alterations, including inflammation, hypoxia and fibrosis. The present study investigated whether HFD-induced MetS might also alter bladder structure and function. Testosterone and the farnesoid X receptor (FXR) agonist INT-747, were evaluated for possible effects on HFD bladder. MetS rabbits develop bladder alterations, including fibrosis (reduced muscle/fiber ratio), hypoxia [2-fold increase as compared to regular diet (RD) group], low-grade inflammation (increased leukocyte infiltration and inflammatory markers) and RhoA/ROCK hyperactivity. Bladder strips from HFD rabbits, pre-contracted with carbachol, showed an overactive response to the selective ROCK inhibitor Y-27632. All these HFD-induced bladder alterations were partially blunted by testosterone and almost completely reverted by INT-747. Both treatments prevented some MetS features (glucose intolerance and visceral fat increase), thus suggesting that their effects on bladder could be ascribed to an improvement of the metabolic and/or hypogonadal state. However, a pathogenetic role for hypogonadism has been ruled out as GnRH analog-induced hypogonadal rabbits, fed a regular diet, did not show any detectable bladder alterations. In addition, INT-747 did not revert the MetS-induced hypogonadal state. FXR mRNA was highly expressed in rabbit bladder and positively associated with visceral fat increase. A direct effect of INT-747 on bladder smooth muscle was further suggested by inhibition of RhoA/ROCK-mediated activity by in vitro experiments on isolated cells. In conclusion, HFD-related MetS features are associated to bladder derangements, which are ameliorated by testosterone or INT-747 administration. INT-747 showed the most marked effects in counteracting MetS-related RhoA/ROCK overactivity, thus opening novel therapeutic opportunities for this drug.
authors.affiliation: Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.forename: Erica
authors.initials: E
authors.lastname: Sarchielli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cellai
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.forename: Ravit
authors.initials: R
authors.lastname: Yehiely-Cohen
authors.forename: Elena
authors.initials: E
authors.lastname: Maneschi
authors.forename: Mauro
authors.initials: M
authors.lastname: Gacci
authors.forename: Marco
authors.initials: M
authors.lastname: Carini
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Gabriella B
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D000728:Androgens / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002465:Cell Movement; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007006:Hypogonadism / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011944:Receptors, Androgen / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D013739:Testosterone / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D017329:Triptorelin Pamoate; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000728:Androgens; D001786:Blood Glucose; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D012333:RNA, Messenger; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D013739:Testosterone; D014280:Triglycerides; D017329:Triptorelin Pamoate; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid