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

Autor(es)

Goncalves, Janaina Garcia ^[1] ; Canale, Daniele ^[1] ; de Braganca, Ana Carolina ^[2] ; Seguro, Antonio Carlos ^[2] ; Shimizu, Maria Heloisa Massola ^[1] ; Volpini, Rildo Aparecido ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Lab Invest Med 12, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Lab Invest Med 12, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN MEDICINE; v. 7, JAN 5 2021.
• Citações Web of Science: 0

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. (AU)

• Processo FAPESP: 15/05513-1 - Avaliação dos eventos envolvidos nas alterações renais associadas aos modelos experimentais de injúria renal aguda isquêmica, nefrectomia 5/6 e nefrotoxicidade por Anfotericina B: influência da deficiência de vitamina D
• Beneficiário: Rildo Aparecido Volpini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/12297-1 - Análise de eventos alternativos envolvidos na formação da fibrose renal em ratos deficientes em vitamina D submetidos à nefrectomia 5/6
• Beneficiário: Rildo Aparecido Volpini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/04930-6 - Estudo da reposição da vitamina D na evolução da injúria renal aguda pós isquêmica em ratos deficientes em vitamina D
• Beneficiário: Ana Carolina de Bragança Viciana
• Modalidade de apoio: Auxílio à Pesquisa - Regular