Potential role of Akt signaling in chronic kidney disease

Lan, Aiping; Du, Jie

doi:10.1093/ndt/gfu196

Cited by 88 publications

(69 citation statements)

References 128 publications

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“…Previous studies suggest that Akt regulates transcriptional activity of NFκB by inducing phosphorylation and subsequent degradation of IκB [28,29]. In this study, we applied Akt inhibitor triciribine [30], and found that Akt inhibition decreased ADR-induced nuclear translocation of NFκB and cellular apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 67%

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

Zhang

Wang

Ren

et al. 2016

Cell Physiol Biochem

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Background/Aims: Although increased expression and gain function of transient receptor potential cation channel 6 (TRPC6) has been associated with the pathogenesis of some proteinuric glomerular diseases, it remains elusive how TRPC6 participates in the process of podocyte damage. Methods: The potential signaling responsible for TRPC6 activation was investigated using immunoblot assays in an in vitro podocyte injury model induced by Adriamycin (ADR). Podocyte apoptosis was measured using FITC-conjugated Annexin V and Propidium Iodide staining. The channel activity of TRPC6 was assessed using the Ca²⁺ influx assay. Results: Increase of TRPC6 expression was detected in ADR-treated podocytes, and TRPC6 knockdown significantly decreased ADR-induced podocytes apoptosis. Following ADR treatment, phospho-mTOR^Ser2481 and phospho-Akt^Ser473 was significantly increased in a time-dependent manner, whereas phospho-mTOR^Ser2448 and phospho-p70S6K^Thr389 showed no change. ADR-induced apoptosis was prevented by ku0063794 (a dual mTOR complexes inhibitor), not by rapamycin (a specific mTORC1 inhibitor). Furthermore, nuclear translocation of NFκB/p65 was detected in ADR-treated podocytes, which was prevented by an Akt inhibitor triciribine. Of note, NFκB inhibitor PDTC prevented ADR-induced increase of TRPC6, and decreased ADR-induced apoptosis. We found that Akt activation and NFκB nuclear translocation was significantly inhibited by knockdown of mTORC2 protein Rictor, not by mTORC1 protein Raptor. In comparison with control, the Ca²⁺ influx was significantly increased in ADR-treated podocytes, which was remarkably prevented by TRPC6 knockdown. ADR-induced increase of TRPC6 channel activity was dramatically prevented by ku0063794, but not by rapamycin. Additionally, knockdown of Rictor, not Raptor, prevented ADR-induced increase of the Ca²⁺ influx. Moreover, the application of NFκB inhibitor PDTC also prevented the Ca²⁺ influx in ADR-treated podocytes. Conclusions: Our findings revealed that the mTORC2/Akt/NFκB pathway-mediated activation of TRPC6 participates in ADR-induced podocyte apoptosis.

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Section: Discussionmentioning

confidence: 67%

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

Zhang

Wang

Ren

et al. 2016

Cell Physiol Biochem

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“…However, downregulation of nephrin, podocin, and CD2AP by activated AKT in morphine treated mice is a contradiction to the evidence that nephrin, podocin, and CD2AP themselves activate AKT via activation of PI3K to promote survival of podocytes [165]. It is pertinent to note that PI3K/AKT signaling can contribute to hypertrophy of mesangial cells upon activation by TGF- β 1 [166], whereas podocytes may also undergo hypertrophic change in response to high glucose, intraglomerular pressure, and Ang II (Figure 3) [167]. Although ROS can activate PI3K/AKT signaling pathway by inducing AKT phosphorylation [54, 168], they can also be accountable for inactivation of AKT by its diminished phosphorylation [103, 169, 170].…”

Section: Mechanisms Of Ros-mediated Glomerular Renal Injury In Diamentioning

confidence: 99%

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

Fakhruddin

Alanazi

Jackson

2017

Journal of Diabetes Research

229

177

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Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure.

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“…Tight regulation between TG synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent lipid accumulation and/or depletion from cells (Mantzaris et al, 2011). Activation of AMP-activated protein kinase (AMPK) and AKT (also known as protein kinase B, PKB) regulates lipid metabolism by stimulating fatty acid uptake and promoting energy use by increasing total cellular ATP content via glycolysis and oxidative phosphorylation control (Bellacosa et al, 1991;Lan and Du, 2015). In addition, AMPK stimulation has been reported to restore lipid metabolism disorder in ob/ob mice (Samovski et al, 2015;Zeng et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Perfluorooctanoic acid exposure alters polyunsaturated fatty acid composition, induces oxidative stress and activates the AKT/AMPK pathway in mouse epididymis

Pan

Sheng

et al. 2016

Chemosphere

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Potential role of Akt signaling in chronic kidney disease

Cited by 88 publications

References 128 publications

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

Perfluorooctanoic acid exposure alters polyunsaturated fatty acid composition, induces oxidative stress and activates the AKT/AMPK pathway in mouse epididymis

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