PhD Scientific Days 2022
Budapest, 6-7 July 2022
Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)
Bradykinin-Induced Detrusor Muscle Contraction Involves both Gαq11- and Gα12/13-Coupled Signaling
Előadó neve
Dr. Borsodi, Kinga
Előadó munkahelye
Institute of Translational Medicine, Semmelweis University
Előadó telefonszáma
+36205740715
Előadó e-mail címe
kingaborsodi@gmail.com
Az előadás címe
Bradykinin-Induced Detrusor Muscle Contraction Involves both Gαq11- and Gα12/13-Coupled Signaling
Szerző(k) neve és munkahelye
Kinga Borsodi1, Helga Balla1, Péter József Molnár1,2, Ádám Lénárt1, István Kenessey3, András Horváth2, Attila Keszthelyi2, Miklós Romics2, Attila Majoros2, Péter Nyirády2, Stefan Offermanns4, Zoltán Benyó1*
1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Department of Urology, Semmelweis University, Budapest, Hungary
3 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
4 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Bemutatás módja
Szóbeli
Szekció
Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)
Language of the presentation
English
Preferred session
Theoretical and Translational Medicine
Összefoglaló szövege
Introduction: Urinary bladder dysfunctins are getting more prevalent due to the aging population. The exact pathomechanisms of these disorders are often unclear, although there is accumulating evidence on the prominent role of inflammatory mediators. Accordingly, the nonapeptid bradykinin (BK) has been proposed in the regulation of bladder tone and implicated in the pathophysiology of detrusor overactivity. Our study aimed to elucidate the signaling pathways of BK-induced detrusor muscle contraction with the goal of identifying potential novel therapeutic targets of its disorders.
Methods: Experiments have been carried out on bladders isolated from wild-type or genetically modified [smooth muscle-specific inducible knockout (KO): Gαq/11-KO, Gα12/13-KO and constitutive KO: thromboxane prostanoid (TP) receptor-KO, cyclooxygenase-1 (COX-1)-KO] mice and on human bladder samples. Contractions of detrusor strips were measured by myography.
Results: BK induced concentration-dependent contractions in both murine and human bladders, which were independent of secondary release of acetylcholine, ATP, or prostanoid mediators. The B2 receptor antagonist HOE-140 markedly diminished, whereas the B1 receptor antagonist R-715 did not alter BK’s contractile effect in both species. Consistently with these findings, introducing the agonist of B2 but not B1 receptors induced contractions of the same magnitude as BK. Interestingly, both Gαq/11- and Gα12/13-KO murine bladders showed reduced response to BK, indicating that simultaneous activation of both pathways is required for the contraction. Furthermore, the Rho-kinase (ROCK) inhibitor Y-27632 markedly decreased contractions in both murine and human bladders.
Conclusion: These results indicate that BK evokes contractions in murine and human bladder smooth muscle, acting primarily on B2 receptors. Our data gained from the smooth muscle-specific Gαq/11-KO and Gα12/13-KO mouse bladders proved that Gαq/11-coupled and Gα12/13-RhoA-ROCK signaling appear to mediate the BK-induced contractions simultaneously. Furthermore, inhibition of ROCK reduces the contractions in both species, identifying this enzyme, together with B2 receptor, as potential targets for treating voiding disorders associated with enhanced BK release.
Funding: NKFIH K-125174, K-135683 and K-139230 and EFOP-3.6.3-VEKOP-16-2017-00009 grants.
University and Doctoral School
Semmelweis University, Doctoral School of Theoretical and Translational Medicine
Supervisor
Zoltán Benyó, MD, PhD, DSc
Publication of my abstract
I do not give consent to the publication of my abstract on the website of the congress.
Kind
Szabad
Status
elfogadva
Accepted presentation method
szóbeli
Előadás fájl jóváhagyás
nem rendelkezett róla
Előadó
4811
Start
10:00
End
10:15
Authors (legacy)
Kinga Borsodi1, Helga Balla1, Péter József Molnár1,2, Ádám Lénárt1, István Kenessey3, András Horváth2, Attila Keszthelyi2, Miklós Romics2, Attila Majoros2, Péter Nyirády2, Stefan Offermanns4, Zoltán Benyó1*
1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Department of Urology, Semmelweis University, Budapest, Hungary
3 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
4 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany