PhD Scientific Days 2024

Poster Session K - Theoretical and Translational Medicine 2.

Bradykinin-induced detrusor muscle contraction involves both Gαq/11- and Gα12/13-coupled signaling

Előadó neve

Dr. Borsodi, Kinga, PhD

Neptun code

IWA1O0

Előadó munkahelye

Institute of Translational Medicine, Semmelweis University, Budapest, Hungary

Előadó telefonszáma

06205740715

Előadó e-mail címe

kingaborsodi@gmail.com

Az előadás címe

Bradykinin-induced detrusor muscle contraction involves both Gαq/11- and Gα12/13-coupled signaling

Szerző(k) neve és munkahelye

Kinga Borsodi¹, Helga Balla¹, Péter József Molnár², Ádám Lénárt¹, István Kenessey³, András Horváth⁴, Attila Keszthelyi⁴, Miklós Romics⁴, Attila Majoros⁴, Péter Nyirády⁴, Stefan Offermanns⁵, Zoltán Benyó⁶

1: Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2: Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; Department of Urology, Semmelweis University, Budapest, Hungary
3: Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary
4: Department of Urology, Semmelweis University, Budapest, Hungary
5: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
6: Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group

Bemutatás módja

Poszter

Szekció

Poster Session K - Theoretical and Translational Medicine 2.

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, EFOP-3.6.3-VEKOP-16-2017-00009 and ÚNKP-23-4-I grants

University

Semmelweis University

Supervisor

Zoltán Benyó, MD, PhD, DSc

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

4811

Start

16:50

End

16:53