Identification of potential therapeutic targets in hypertension-associated bladder dysfunction.
OBJECTIVE
To investigate differential gene expression profiles in the bladder of spontaneously hypertensive rat (SHR), as the underlying mechanisms involved in hypertension-associated bladder dysfunction remain to be clarified.


METHODS
SHR and normotensive Wistar-Kyoto (WKY) rats were distributed initially in three groups: group 1 received doxazosin (30 mg/kg/day); group 2 received nifedipine (30 mg/kg/day); and group 3 received the vehicle orally for 4 weeks. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential biological relevance were verified by real-time reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Voiding frequency was significantly higher, and mean voided volume was significantly lower in untreated SHRs than untreated WKY rats. Microarray analysis revealed that 25 of the differentially expressed genes in untreated SHRs compared to untreated WKY rats were related to G(s), G(i), G(q) and G(12/13) signalling, calcium handling, ion transport and smooth muscle-related genes. Furthermore, RT-PCR data, in accord with the microarray analysis, indicated that untreated SHRs had lower mRNA expression levels of Adcy2, Adcy3, Rgs2, Rgs3, Rgs4 and Arhgdia, and higher mRNA expression levels of Arhgef1, Arhgef11, Arhgef12, Geft, Rock1 and Rock2 than untreated WKY rats. The differential alterations in the micturition patterns and in the expression of several genes related to G-protein signalling pathway observed in SHRs were attenuated by treatment with doxazosin, but not nifedipine.


CONCLUSIONS
Our data suggest that differential alterations in the expression of several genes related to G(s), G(q) and G(12/13) signalling pathways in the SHR bladder might be important in hypertension-associated bladder dysfunction.
Yono
Makoto
M
Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. yonomakoto@hotmail.com
Yoshida
Masaki
M
Yamamoto
Yasuhiro
Y
Imanishi
Aya
A
Fukagawa
Atsushi
A
Latifpour
Jamshid
J
Eto
Masatoshi
M
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D017292:Doxazosin / Q000627:therapeutic use*; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D009543:Nifedipine / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D001745:Urinary Bladder Diseases / Q000150:complications / Q000188:drug therapy / Q000235:genetics*
D000959:Antihypertensive Agents; D009543:Nifedipine; D017292:Doxazosin