Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-delta/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity

Autor(es)

Cardoso, Vanessa Gerolde ^[1] ; Goncalves, Guilherme Lopes ^[1] ; Costa-Pessoa, Juliana Martins ^[1] ; Thieme, Karina ^[2] ; Lins, Bruna Bezerra ^[1] ; Malavazzi Casare, Fernando Augusto ^[1] ; de Ponte, Mariana Charleaux ^[1] ; Saraiva Camara, Niels Olsen ^[3] ; Oliveira-Souza, Maria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Lab Renal Physiol, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Med Sch, Lab Carbohydrates & Radioimmunoassays LIM 18, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BMC Nephrology; v. 19, JUL 13 2018.
• Citações Web of Science: 7

Resumo

Background: Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. In the present study, we investigated whether the chronic effects of Ang II via AT1 receptor (AT1R) would result in endoplasmic reticulum (ER) stress/PKC-delta/p38 MAPK stimulation, and consequently podocyte apoptosis. Methods: Wistar rats were treated with Ang II (200 ng.kg(-1).min(-1), 42 days) and or losartan (10 mg.kg(-1).day(-1), 14 days). Immortalized mouse podocyte were treated with 1 mu M Ang II and/or losartan (1 mu M) or SB203580 (0.1 mu M) (AT1 receptor antagonist and p38 MAPK inhibitor) for 24 h. Kidney sections and cultured podocytes were used to evaluate protein expression by immunofluorescence and immunoblotting. Apoptosis was evaluated by flow cytometry and intracellular pH (pHi) was analyzed using microscopy combined with the fluorescent probe BCECF/AM. Results: Compared with controls, Ang II via AT1R increased chaperone GRP 78/Bip protein expression in rat glomeruli (p < 0.001) as well as in podocyte culture (p < 0.01); increased phosphorylated eIf2-alpha (p < 0.05), PKC-delta (p < 0.01) and p38 MAPK (p < 0.001) protein expression. Furthermore, Ang II induced p38 MAPK-mediated late apoptosis and increased the Bax/Bcl-2 ratio (p < 0.001). Simultaneously, Ang II via AT1R induced p38 MAPK-NHE1-mediated increase of pHi recovery rate after acid loading. Conclusion: Together, our results indicate that Ang II-induced podocyte apoptosis is associated with AT1R/ER stress/PKC-delta/p38 MAPK axis and enhanced NHE1-mediated pHi recovery rate. (AU)

• Processo FAPESP: 14/19154-0 - Efeito da angiotensina II nos mecanismos celulares envolvidos na injúria de podócitos
• Beneficiário: Vanessa Gerolde Cardoso
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 13/23087-4 - Estudo molecular e funcional de transportadores de membrana
• Beneficiário: Gerhard Malnic
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/19569-3 - Efeitos da endotelina 3 e da leptina na morfologia e função renal in vivo: participação do sistema renina-angiotensina intrarrenal
• Beneficiário: Maria Oliveira de Souza
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/14022-0 - Efeitos da interação do sistema-renina-angiotensina-aldosterona e endotelinas-1 e 3 sobre a função renal
• Beneficiário: Fernando Augusto Malavazzi Casare
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/17251-9 - Efeitos da administração crônica de albumina modificada por glicação avançada (AGE) sobre o tecido renal: caracterização do perfil inflamatório, antioxidante e epigenético
• Beneficiário: Karina Thieme
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/02020-0 - Mecanismos envolvidos na transição da injúria renal aguda pós-isquêmica para a doença renal crônica: contribuição da angiotensina II e da albumina
• Beneficiário: Maria Oliveira de Souza
• Modalidade de apoio: Auxílio à Pesquisa - Regular