Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury

Abstract

Numerous studies have reported that angiotensin (Ang) II, nephrin, and podocin serve pivotal roles in podocyte injury, and thus can lead to the occurrence of proteinuria and the progression of kidney diseases. This study aimed to investigate the effects of Ang II on the production of nephrin and podocin, and their relationship with podocyte injury. We also aimed to determine whether nephrin, podocin and caspase-9 production depends on the PI3K/Akt/nuclear factor (NF)-κB signaling pathway in cultured mouse podocytes. We treated mouse podocytes with different doses of Ang II (10−9, 10−8, 10−7 and 10−6 mol/l) for 12, 24, and 48 h to analyse cell viability, and at 10−6 mol/l Ang II for 12, 24, and 48 h to evaluate cell apoptosis. Cells were treated with 10−6 mol/l of Ang II and/or LY294002 (inhibitor of Akt) or 740Y-P (activator of PI3K) for 48 h to detect Akt, phosphorylated (phospho)-Akt, p65 NF-κB, and phospho-p65 NF-κB, nephrin, podocin and caspase-9 expression, and podocyte apoptosis. Treatment with Ang II suppressed the viability and promoted the apoptosis of podocytes in a dose- and time-dependent manner. Ang II decreased phospho-Akt, phospho-p65 NF-κB, nephrin, and podocin and increased caspase-9 expression, while podocyte apoptosis was promoted. LY294002 further enhanced Ang II-induced downregulation of Akt and p65 NF-κB activation, as well as upregulation of caspase-9 mRNA and protein, and promoted the apoptosis of podocytes. Of note, 740Y-P restored Ang II-induced downregulation of Akt and p65 NF-κB activation, and upregulation of caspase-9, and decreased podocyte apoptosis. Interestingly, LY294002 and 740Y-P were determined to have no notable effects on the expression of nephrin and podocin. The data suggested that Ang II could regulate the expression of nephrin, podocin and caspase-9. Collectively, our findings suggested that the PI3K/Akt/NF-κB survival axis may serve a pivotal role in podocyte injury.

Olive leaf extract attenuates adriamycin‐induced focal segmental glomerulosclerosis in spontaneously hypertensive rats via suppression of oxidative stress, hyperlipidemia, and fibrosis

“…underlying injury and dysfunction of these cells (Wang, Fu, Senouthai, & You, 2019). The overproduction of angiotensin II is present in SHR (Fan et al, 2014), thus we assumed that under ADR-induced oxidative stress the reduction of p65 subunit by angiotensin II could be involved in podocytes injury and glomerulosclerosis.…”

“…Furthermore, we found that TNF‐α protein expression was also decreased in these rats, which might be a consequence of the absence of p65 subunit (Nediani et al, 2019). The decrease of NF‐kB p65 protein induced by angiotensin II in the podocytes indicated to a possible mechanism underlying injury and dysfunction of these cells (Wang, Fu, Senouthai, & You, 2019). The overproduction of angiotensin II is present in SHR (Fan et al, 2014), thus we assumed that under ADR‐induced oxidative stress the reduction of p65 subunit by angiotensin II could be involved in podocytes injury and glomerulosclerosis.…”

Fractalkine deficiency attenuates LPS-induced acute kidney injury and podocyte apoptosis by targeting the PI3K/Akt signal pathway

“…Inhibition of PI3K/Akt signal suppressed podocytes mesenchymal trans-differentiation [29]. The previous study of our research group have demonstrated that the activation of PI3K/Akt signal effectively suppressed AngII-induced podocytes apoptosis [30]. In our vivo model, the phosphorylation of Akt was inhibited by LPS while activated by FKN Depletion.…”

Beneficial effects of procyanidin B2 on adriamycin-induced nephrotic syndrome mice: the multi-action mechanism for ameliorating glomerular permselectivity injury

“…The NF-κB signaling events in NS can be triggered by various stimulators, including nephrin deficiency and excessive ROS, ultimately leading to the activation of the IκB kinase complex. 106,113,114 NF-κB is activated following activation of the IκB kinase complex and phosphorylation of IκBs, subsequently leading to degradation of IκBs and liberation of NF-κB from IκB proteins. 115 As one key upstream kinase, the IκB kinase complex can be recruited to the TNF-receptor 1 proximal complex and activated by TNFα.…”