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Open Access 01-12-2018 | Research article

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

Authors: Vanessa Gerolde Cardoso, Guilherme Lopes Gonçalves, Juliana Martins Costa-Pessoa, Karina Thieme, Bruna Bezerra Lins, Fernando Augusto Malavazzi Casare, Mariana Charleaux de Ponte, Niels Olsen Saraiva Camara, Maria Oliveira-Souza

Published in: BMC Nephrology | Issue 1/2018

Abstract

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 μM Ang II and/or losartan (1 μM) or SB203580 (0.1 μM) (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-α (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.

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Title: Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-δ/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity
Authors: Vanessa Gerolde Cardoso
Guilherme Lopes Gonçalves
Juliana Martins Costa-Pessoa
Karina Thieme
Bruna Bezerra Lins
Fernando Augusto Malavazzi Casare
Mariana Charleaux de Ponte
Niels Olsen Saraiva Camara
Maria Oliveira-Souza
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Nephrology / Issue 1/2018
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-018-0968-4

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

Abstract

Background

Methods

Results

Conclusion

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Abstract

Background

Methods

Results

Conclusion

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