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

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.

The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy

“…Moreover, PKCd activation has also been reported to be related to therapy resistance. For instance, a study indicated that fractionated radiation induced an increase in the glioma-initiating cell population and less sensitivity to cancer treatment and reported to be phosphorylated and activated by PKCd (30,31,36,37), our data showed that only Akt but neither p38 nor JNK1/2 was involved in tumor repopulation in a PKCd-dependent way. Further studies will be needed to understand the preferential use of Akt as the downstream effector of PKCd over the other two.…”

“…The activation of PKCd after ionizing radiation has been shown to affect the function of several signal transduction proteins. Akt, p38 kinase, and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK or JNK1/2) were shown to act downstream of protein kinases and be involved in regulating the cell cycle, cell proliferation, cell survival, and carcinogenesis (30)(31)(32)(33)(34)(35)(36)(37)(38). Therefore, we decided to investigate the activities of those proteins in irradiated dying cells to see if they were involved in tumor repopulation during radiotherapy.…”

Angiotensin II promotes podocyte injury by activating Arf6-Erk1/2-Nox4 signaling pathway

“…Recent studies have shown that Ang II can activate and/or trigger various cellular events (e.g. oxidative stress and reactive oxygen species overproduction, endoplasmic reticulum stress, autophagy and mitochondrial dysfunction), thus resulting in cytoskeletal rearrangement and podocyte apoptosis [4][5][6][7][8][9]. Notably, NADPH oxidase (Nox) plays a critical role in driving reactive oxygen species (ROS) production.…”

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID‐19

“…Increasing the effects of angiotensin II on the lung interstitium can promote apoptosis, which, in turn, initiates an inflammatory process with release of proinflammatory cytokines, establishing a self‐powered cascade (Cardoso et al, 2018). In certain patients, this process reaches such clinical relevance that requires external oxygen supply and in severe cases an Acute Respiratory Distress Syndrome (ARDS) ensues (this correlates with an acute release ‐storm‐ of cytokines) (Ware & Matthay, 2000).…”