The Blockade of TACE-Dependent EGF Receptor Activation by Losartan-Erlotinib Combination Attenuates Renal Fibrosis Formation in 5/6-Nephrectomized Rats Under Vitamin D Deficiency

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art_GONCALVES_The_Blockade_of_TACEDependent_EGF_Receptor_Activation_by_2021.PDF (4.47 MB)
Citações na Scopus
2
Tipo de produção
article
Data de publicação
2021
DOI
Scopus
Web of Science
PubMed
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Título do Volume
Editora
FRONTIERS MEDIA SA
Autores
Citação
FRONTIERS IN MEDICINE, v.7, article ID 609158, 15p, 2021
Projetos de Pesquisa
Unidades Organizacionais
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Resumo
Chronic kidney disease (CKD) has been considered a major public health issue. In addition to cardiovascular diseases and infections, hypovitaminosis D has been considered a non-traditional aggravating factor for CKD progression. Interstitial fibrosis is a hallmark of CKD strongly correlated with deterioration of renal function. Transforming growth factor beta (TGF-beta) is the major regulatory profibrotic cytokine in CKD. Many injurious stimuli converge on the TGF-beta pathway, which has context-dependent pleiotropic effects and interacts with several related renal fibrosis formation (RFF) pathways. Epidermal growth factor receptor (EGFR) is critically involved in CKD progression, exerting a pathogenic role in RFF associated with TGF-beta-related fibrogenesis. Among others, EGFR pathway can be activated by a disintegrin and a metalloproteinase known as tumor necrosis factor alpha-converting enzyme (TACE). Currently no effective therapy is available to completely arrest RFF and slow the progression of CKD. Therefore, we investigated the effects of a double treatment with losartan potassium (L), an AT1R antagonist, and the tyrosine kinase inhibitor erlotinib (E) on the alternative pathway of RFF related to TACE-dependent EGFR activation in 5/6-nephrectomized rats under vitamin D deficiency (D). During the 90-day protocol, male Wistar rats under D, were submitted to 5/6 nephrectomy (N) on day 30 and randomized into four groups: N+D, no treatment; N+D+L, received losartan (50 mg/kg/day); N+D+E, received erlotinib (6 mg/kg/day); N+D+L+E received losartan+erlotinib treatment. N+D+L+E data demonstrated that the double treatment with losartan+erlotinib not only blocked the TACE-dependent EGF receptor activation but also prevented the expression of TGF-beta, protecting against RFF. This renoprotection by losartan+erlotinib was corroborated by a lower expression of ECM proteins and markers of phenotypic alteration as well as a lesser inflammatory cell infiltrate. Although erlotinib alone has been emerging as a renoprotective drug, its association with losartan should be considered as a potential therapeutic strategy on the modulation of RFF.
Palavras-chave
chronic kidney disease, TACE, renal fibrosis, vitamin D deficiency, erlotinib, experimental model, EGF receptor (EGFR), EGF (epidermal growth factor)
URI
https://observatorio.fm.usp.br/handle/OPI/39490
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Coleções
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - LIM/12
Artigos e Materiais de Revistas Científicas - ODS/03