Abstract
BackgroundAngiotensin 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.MethodsWistar 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.ResultsCompared 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.ConclusionTogether, 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.
Highlights
Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis
Chronic treatment with Ang II leads to endoplasmic reticulum (ER) stress and Protein kinase C delta (PKC-δ) phosphorylation in podocytes Since Ang II induced an increase in glomerular and podocytes GRP 78 expression in vivo, we decided to further study its effects and the activated intracellular signaling pathways using an in vitro model of cultured podocytes
We explored whether Ang II or p38 mitogen-activated protein kinase (MAPK) played a role in podocyte apoptosis
Summary
Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. Numerous studies have demonstrated a relevant contribution of podocytes in the pathogenesis and progression of chronic kidney diseases [2,3,4,5,6,7] Along this line, slit diaphragm disruption and foot process effacement have been considered early manifestations of progressive podocyte damage and cell loss [8], resulting in glomerular hemodynamic disorders, proteinuria and glomerulosclerosis [9,10,11,12]. At high circulating concentrations, Ang II stimulates intrarenal RAS and induces glomerular injury, which progresses toward end-stage renal disease [7, 13] Podocytes express both types of Ang II receptors (AT1R and AT2R) and have been shown to be target cells of the peptide [14]. ROS production is closely related to ER stress, protein kinase C delta (PKC-δ) and p38 mitogen-activated protein kinase (p38 MAPK) activation, and together, these events are associated with apoptotic responses [18,19,20,21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
