Tamoxifen attenuates renal fibrosis in human kidney slices and rats subjected to unilateral ureteral obstruction

Tingskov, Stine Julie; Jensen, Michael Schou; Pedersen, Casper; Araujo, Isabela Bastos Binotti Abreu de; Mutsaers, Henricus A M; Nørregaard, Rikke

doi:10.1016/j.biopha.2020.111003

Cited by 15 publications

(23 citation statements)

References 28 publications

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“…More recently, TAM was described to exert important anti brotic effects in the experimental model of unilateral ureteral obstruction (UUO) in mice. Similarly, to the observed in the present study, TAM treatment reduced the production and deposition of ECM proteins in UUO kidneys, as well as the renal deposition of bronectin and collagen [28,29]. Although the exact mechanisms involved in the anti-in ammatory and anti brotic effects of TAM are still poorly known, it exerts undoubted suppressive effects on broblast proliferation, activation and ECM secretion, evidenced in our in vitro results, which corroborate the current literature [30].…”

Section: Discussionsupporting

confidence: 92%

Tamoxifen, associated to the conservative CKD treatment, promoted additional antifibrotic effects on experimental hypertensive nephrosclerosis

Fanelli

Ornellas

Celestrino

et al. 2022

Preprint

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CKD progression depends on the activation of an intricate set of hemodynamic and inflammatory mechanisms, promoting renal leukocyte infiltration, inflammation and fibrosis, leading to renal function loss. There are currently no specific drugs to detain renal fibrogenesis, which is a common end-point for different nephropathies. Clinical therapy for CKD is mostly based on the management of hypertension and proteinuria, partially achieved with renin-angiotensin-aldosterone system (RAAS) blockers, and the control of inflammation by immunosuppressive drugs. The aim of the present study was to verify if the administration of tamoxifen (TAM), an estrogen receptor modulator, clinically employed in the treatment of breast cancer and predicted to exert antifibrotic effects, would promote additional benefits when associated to a currently used therapeutic scheme for the conservative management of experimental CKD. Wistar rats underwent the NAME model of hypertensive nephrosclerosis, obtained by daily oral administration of a nitric oxide synthesis inhibitor, associated to dietary sodium overload. The therapeutic association of TAM to losartan (LOS), and mofetil mycophenolate (MMF) effectively reduced the severe hypertension, marked albuminuria and glomerular damage exhibited by NAME animals. Moreover, the association also succeeded in limiting renal inflammation in this model, and promoted further reduction of ECM interstitial accumulation and renal fibrosis, compared to the monotherapies. According to our results, the association of TAM to the currently used conservative treatment of CKD added significant antifibrotic effects both in vivo and in vitro, and may represent an alternative to slow the progression of chronic nephropathy.

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Section: Discussionsupporting

confidence: 92%

Tamoxifen, associated to the conservative CKD treatment, promoted additional antifibrotic effects on experimental hypertensive nephrosclerosis

Fanelli

Ornellas

Celestrino

et al. 2022

Preprint

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“…It should be noted that although it is widely used as a renal fibrosis model, UUO requires aggressive surgery that leads to a rapid interstitial inflammation at difference with the slow progression observed in humans 17,45 . Nevertheless, this model has proven useful both for the identification of biomarkers and for the development of new treatments 46‐48 . Furthermore, our study documents that bemcentinib was able to improve mitochondrial function at the molecular level despite the intrusiveness of the experimental method.…”

Section: Discussionmentioning

confidence: 55%

“…17,45 Nevertheless, this model has proven useful both for the identification of biomarkers and for the development of new treatments. [46][47][48] Furthermore, our study documents that bemcentinib was able to improve mitochondrial function at the molecular level despite the intrusiveness of the experimental method.…”

Section: Discussionmentioning

confidence: 60%

Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

Hoel

Osman

Hoel

et al. 2021

J Cellular Molecular Medi

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Renal fibrosis is a progressive histological manifestation leading to chronic kidney disease (CKD) and associated with mitochondrial dysfunction. In previous work, we showed that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, reduced fibrosis development. In this study, to investigate its effects on mitochondrial dysfunction in renal fibrosis, we analysed genome‐wide transcriptomics data from a unilateral ureter obstruction (UUO) murine model in the presence or absence of bemcentinib (n = 6 per group) and SHAM‐operated (n = 4) mice. Kidney ligation resulted in dysregulation of mitochondria‐related pathways, with a significant reduction in the expression of oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), citric acid cycle (TCA), response to reactive oxygen species and amino acid metabolism‐related genes. Bemcentinib treatment increased the expression of these genes. In contrast, AKT/PI3K signalling pathway genes were up‐regulated upon UUO, but bemcentinib largely inhibited their expression. At the functional level, ligation reduced mitochondrial biomass, which was increased upon bemcentinib treatment. Serum metabolomics analysis also showed a normalizing amino acid profile in UUO, compared with SHAM‐operated mice following bemcentinib treatment. Our data suggest that mitochondria and mitochondria‐related pathways are dramatically affected by UUO surgery and treatment with Axl‐inhibitor bemcentinib partially reverses these effects.

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“…During experiments, the slices were treated for 48 h with 10 ng/ml recombinant human transforming growth factor-β1 (TGF-β; H8541, Sigma-Aldrich) in the absence or presence of butaprost (50 µM; a selective prostaglandin E 2 [PGE 2 ] EP 2 receptor agonist; 13741, Cayman), SC-19220 (225 µM; a selective PGE 2 EP 1 receptor antagonist; S3065, Sigma-Aldrich) or tamoxifen (5 nM; a selective estrogen receptor modulator; T5648, Sigma-Aldrich). Of note, tamoxifen was only present during the final 6 h. We have previously demonstrated the anti-fibrotic activity of these compounds using cell- and animal models as well as human PCKS [ 5 – 7 ].…”

Section: Methodsmentioning

confidence: 99%

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

et al. 2023

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Objective Renal fibrosis is one of the main pathophysiological processes underlying the progression of chronic kidney disease and kidney allograft failure. In the past decades, overwhelming efforts have been undertaken to find druggable targets for the treatment of renal fibrosis, mainly using cell- and animal models. However, the latter often do not adequately reflect human pathogenesis, obtained results differ per strain within a given species, and the models are associated with considerable discomfort for the animals. Therefore, the objective of this study is to implement the 3Rs in renal fibrosis research by establishing an animal-free drug screening platform for renal fibrosis based on human precision-cut kidney slices (PCKS) and by limiting the use of reagents that are associated with significant animal welfare concerns. Results Using Western blotting and gene expression arrays, we show that transforming growth factor-β (TGF-β) induced fibrosis in human PCKS. In addition, our results demonstrated that butaprost, SC-19220 and tamoxifen – all putative anti-fibrotic compounds – altered TGF-β-induced pro-fibrotic gene expression in human PCKS. Moreover, we observed that all compounds modulated fairly distinct sets of genes, however they all impacted TGF-β/SMAD signaling. In conclusion, this study revealed that it is feasible to use an animal-free approach to test drug efficacy and elucidate mechanisms of action.

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Tamoxifen attenuates renal fibrosis in human kidney slices and rats subjected to unilateral ureteral obstruction

Cited by 15 publications

References 28 publications

Tamoxifen, associated to the conservative CKD treatment, promoted additional antifibrotic effects on experimental hypertensive nephrosclerosis

Tamoxifen, associated to the conservative CKD treatment, promoted additional antifibrotic effects on experimental hypertensive nephrosclerosis

Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

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