Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model

Judit Prat-Duran; Isabela Bastos Binotti Abreu De Araujo; Nina Juste; Estéfano Pinilla; Francisco J. Rios; Augusto C. Montezano; Rhian M. Touyz; Ulf Simonsen; Rikke Nørregaard; Niels Henrik Buus

doi:10.1016/j.ejphar.2024.177037

Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model

Judit Prat-Duran^*, Isabela Bastos Binotti Abreu De Araujo, Nina Juste, Estéfano Pinilla, Francisco J. Rios, Augusto C. Montezano, Rhian M. Touyz, Ulf Simonsen, Rikke Nørregaard, Niels Henrik Buus

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

2 Citations (Scopus)

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 h, 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.

Original language	English
Article number	177037
Journal	European Journal of Pharmacology
Volume	984
Number of pages	12
ISSN	0014-2999
DOIs	https://doi.org/10.1016/j.ejphar.2024.177037
Publication status	Published - 5 Dec 2024

Keywords

Fibrosis
Kidney disease
Pharmacology
Transglutaminase 2
Unilateral ureteral obstruction model

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10.1016/j.ejphar.2024.177037

Cite this

Prat-Duran, J., Binotti Abreu De Araujo, I. B., Juste, N., Pinilla, E., Rios, F. J., Montezano, A. C., Touyz, R. M., Simonsen, U., Nørregaard, R., & Buus, N. H. (2024). Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model. European Journal of Pharmacology, 984, Article 177037. https://doi.org/10.1016/j.ejphar.2024.177037

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title = "Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model",

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 h, 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.",

keywords = "Fibrosis, Kidney disease, Pharmacology, Transglutaminase 2, Unilateral ureteral obstruction model",

author = "Judit Prat-Duran and {Binotti Abreu De Araujo}, {Isabela Bastos} and Nina Juste and Est{\'e}fano Pinilla and Rios, {Francisco J.} and Montezano, {Augusto C.} and Touyz, {Rhian M.} and Ulf Simonsen and Rikke N{\o}rregaard and Buus, {Niels Henrik}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = dec,

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doi = "10.1016/j.ejphar.2024.177037",

language = "English",

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Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model. / Prat-Duran, Judit ; Binotti Abreu De Araujo, Isabela Bastos ; Juste, Nina et al.
In: European Journal of Pharmacology, Vol. 984, 177037, 05.12.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model

AU - Prat-Duran, Judit

AU - Binotti Abreu De Araujo, Isabela Bastos

AU - Juste, Nina

AU - Pinilla, Estéfano

AU - Rios, Francisco J.

AU - Montezano, Augusto C.

AU - Touyz, Rhian M.

AU - Simonsen, Ulf

AU - Nørregaard, Rikke

AU - Buus, Niels Henrik

PY - 2024/12/5

Y1 - 2024/12/5

N2 - 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 h, 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.

AB - 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 h, 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.

KW - Fibrosis

KW - Kidney disease

KW - Pharmacology

KW - Transglutaminase 2

KW - Unilateral ureteral obstruction model

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U2 - 10.1016/j.ejphar.2024.177037

DO - 10.1016/j.ejphar.2024.177037

M3 - Journal article

C2 - 39369875

AN - SCOPUS:85205519719

SN - 0014-2999

VL - 984

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

M1 - 177037

ER -

Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model

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