The role of hedgehog-interacting protein in maintaining cavernous nerve integrity and adult penile morphology.
BACKGROUND
Sonic hedgehog (SHH) is an essential regulator of smooth muscle apoptosis in the penis that has significant clinical potential as a therapy to suppress post-prostatectomy apoptosis, an underlying cause of erectile dysfunction (ED). Thus an understanding of how SHH signaling is regulated in the adult penis is essential to move the field of ED research forward and to develop new treatment strategies. We propose that hedgehog-interacting protein (HIP), which has been shown to bind SHH protein and to play a role in SHH regulation during embryogenesis of other organs, is a critical regulator of SHH signaling, penile morphology, and apoptosis induction.


OBJECTIVE
We have examined HIP signaling in the penis and cavernous nerve (CN) during postnatal differentiation of the penis, in CN-injured, and a diabetic model of ED.


METHODS
HIP localization/abundance and RNA abundance were examined by immunohistochemical (IHC) analysis and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in Sprague-Dawley rats between the ages of 7 and 92 days old, in CN-injured Sprague-Dawley rats and in BioBreeding/Worcester diabetic rats. HIP signaling was perturbed in the pelvic ganglia and in the penis and TUNEL assay was performed in the penis. CN tie, lidocaine, and anti-kinesin experiments were performed to examine HIP signaling in the CN and penis.


RESULTS
In this study we are the first to demonstrate that HIP undergoes anterograde transport to the penis via the CN, that HIP perturbation in the pelvic ganglia or the penis induces apoptosis, and that HIP plays a role in maintaining CN integrity, penile morphology, and SHH abundance.


CONCLUSIONS
These studies are significant because they show HIP involvement in cross-talk (signaling) between the pelvic ganglia and penis, which is integral for maintenance of penile morphology and they suggest a mechanism of how nerves may regulate target organ morphology and function.
Angeloni
Nicholas L
NL
Department of Urology, Northwestern University Medical School, Chicago, IL 60611, USA.
Bond
Christopher W
CW
Monsivais
Diana
D
Tang
Yi
Y
Podlasek
Carol A
CA
D000818:Animals; D017209:Apoptosis; D007172:Erectile Dysfunction / Q000503:physiopathology*; D053823:Hedgehog Proteins; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide; D010413:Penis / Q000187:drug effects / Q000294:innervation* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D053823:Hedgehog Proteins; D009569:Nitric Oxide; D008012:Lidocaine