1. Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model.
- Author
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Prat-Duran J, Binotti Abreu De Araujo IB, Juste N, Pinilla E, Rios FJ, Montezano AC, Touyz RM, Simonsen U, Nørregaard R, and Buus NH
- Abstract
Background: Transglutaminase 2 (TG2) is a multifunctional enzyme involved in fibrosis by promoting transforming-growth-factor-β1 and crosslinking of extracellular matrix proteins. These functions are dependent on the open conformation, while the closed state of TG2 can induce vasodilation. We explored the putative protective role of TG2 in its closed state on development of renal fibrosis and blood pressure (BP) regulation., Methods: We studied the unilateral ureteral obstruction (UUO) mouse model treated with LDN27219, which promotes the closed conformation of TG2. Mice were subjected to 7 days UUO or sham operation and treated with vehicle (n=10), LDN27219 (15 mg/kg/12 hours, n=9) or candesartan (5 mg/kg/day, n=10) as a clinically comparator. Renal expression of TG2 and pro-fibrotic mediators were evaluated by Western blotting, qPCR and histology, and BP by tail-cuff measurements., Results: Obstructed kidneys showed increased mRNA and protein expression of fibronectin, collagen 3α1 (Col3α1), α-smooth muscle actin and collagen staining. Despite increased renal TG2 mRNA, protein expression was reduced in all UUO groups, but with increased transamidase activity in the vehicle and candesartan groups. LDN27219 reduced mRNA expression of fibronectin and Col3α1, but their protein expression remained unchanged. In contrast to LDN27219, candesartan lowered BP without affecting expression of pro-fibrotic biomarkers., Conclusion: Renal TG2 mRNA and protein expression levels seem dissociated, with transamidase activity being increased. LDN27219 influences kidney pro-fibrotic markers at the mRNA level and attenuates transamidase activity but without affecting collagen content or BP. Our findings suggest that TG2 in its closed conformation has anti-fibrotic effects at the molecular level., Competing Interests: Declaration of Competing Interest ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Estefano Pinilla reports financial support was provided by Erik Hørslev and Birgit Hørslev Fund. Niels Henrik Buus reports financial support was provided by Aarhus University Research Foundation. Estefano Pinilla has patent #EP3607948A1 licensed to Aarhus University. Ulf Simonsen has patent #EP3607948A1 licensed to Aarhus University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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