Albumin overload down-regulates integrin-β1 through reactive oxygen species-endoplasmic reticulum stress pathway in podocytes

Cheng, Yu-Chi; Chen, Chien-An; Chang, Jer‐Ming; Chen, Hung‐Chun

doi:10.1093/jb/mvv020

Cited by 16 publications

(18 citation statements)

References 30 publications

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“…Albumin has been shown to be an ER stress inducer but the underlying mechanisms have not been extensively studied. Others have shown that albumin may provoke inflammasome activation and calcium mobilization in tubular cells while other mechanisms such as reduced expression of the adaptor protein CD2AP, ROS production and activation of the MAPK/caspase‐12 pathway have been reported to be involved in podocyte apoptosis . Of interest, 4‐PBA has been described to decrease fibrosis in chronic proteinuric disease .…”

Section: Discussionmentioning

confidence: 99%

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

et al. 2019

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Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD‐ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines. This downregulation was related to both decreased Klotho transcription and diminished protein half‐life, whereas cleavage by ADAM proteases was not modified. The regulation was albumin specific since it was neither observed in the analbuminemic Col4α3−/− Alport mice nor induced by exposure of kidney epithelial cells to purified immunoglobulins. Albumin induced features of ER stress in renal tubular cells with ATF3/ATF4 activation. ATF3 and ATF4 induction downregulated Klotho through altered transcription mediated by their binding on the Klotho promoter. Inhibiting ER stress with 4‐PBA decreased the effect of albumin on Klotho protein levels without altering mRNA levels, thus mainly abrogating the increased protein degradation. Taken together, albuminuria decreases Klotho expression through increased protein degradation and decreased transcription mediated by ER stress induction. This implies that modulating ER stress may improve proteinuria‐induced alterations of Klotho expression, and hence renal and extrarenal complications associated with Klotho loss.

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Section: Discussionmentioning

confidence: 99%

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

et al. 2019

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“…For example, NF‐kappa B and other pro‐inflammatory transcription factors can induce the activation of downstream integrin β3, leading to podocyte injury and proteinuria . Whereas the expression of integrin β1 in podocyte was considered negatively correlated with the severity of proteinuria . Elevated expression of TGF‐β1 or ROS induced decreased expression of integrin β1, resulting in the production of proteinuria .…”

Section: Discussionmentioning

confidence: 99%

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

Wang

Yin³

et al. 2018

J Cellular Molecular Medi

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Podocyte injury is an early pathological change characteristic of various glomerular diseases, and apoptosis and F‐actin cytoskeletal disruption are typical features of podocyte injury. In this study, we found that adriamycin (ADR) treatment resulted in typical podocyte injury and repressed plectin expression. Restoring plectin expression protected against ADR‐induced podocyte injury whereas siRNA‐mediated plectin silencing produced similar effects as ADR‐induced podocyte injury, suggesting that plectin plays a key role in preventing podocyte injury. Further analysis showed that plectin repression induced significant integrin α6β4, focal adhesion kinase (FAK) and p38 MAPK phosphorylation. Mutating Y1494, a key tyrosine residue in the integrin β4 subunit, blocked FAK and p38 phosphorylation, thereby alleviating podocyte injury. Inhibitor studies demonstrated that FAK Y397 phosphorylation promoted p38 activation, resulting in podocyte apoptosis and F‐actin cytoskeletal disruption. In vivo studies showed that administration of ADR to rats resulted in significantly increased 24‐hour urine protein levels along with decreased plectin expression and activated integrin α6β4, FAK, and p38. Taken together, these findings indicated that plectin protects podocytes from ADR‐induced apoptosis and F‐actin cytoskeletal disruption by inhibiting integrin α6β4/FAK/p38 pathway activation and that plectin may be a therapeutic target for podocyte injury‐related glomerular diseases.

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“…Accumulating evidence suggests that ER stress is tightly linked to oxidative stress [2,6,20]. Furthermore, it has been shown that AOPP-induced ER stress in adipocytes is mediated by the activation of NADPH oxidasedependent ROS generation [43].…”

Section: Discussionmentioning

confidence: 99%

Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress

et al. 2015

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Although podocyte apoptosis has been shown to be induced by the accumulation of advanced oxidation protein products (AOPPs), the mechanisms through which AOPPs trigger apoptosis in these cells remain unclear. In this study, we investigated the role of endoplasmic reticulum (ER) stress in AOPP-induced podocyte apoptosis. AOPP treatment induced overexpression of glucose-regulated protein 78 and CCAAT/enhancer-binding protein-homologous protein (CHOP) in podocytes, indicating that AOPPs induced ER stress. Notably, AOPP-induced increase in the rate of podocyte apoptosis was partly reversed by salubrinal, an ER stress inhibitor, whereas the AOPP effect was reproduced by an inducer of ER stress, thapsigargin, suggesting that AOPPs triggered podocyte apoptosis by inducing ER stress. Furthermore, AOPP-induced reactive oxygen species (ROS) generation, ER stress, and podocyte apoptosis were significantly inhibited by an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, a ROS scavenger, or receptor of advanced glycation end products (RAGE) small interfering RNA (siRNA). Moreover, silencing of the three ER stress sensors, protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring 1 (IRE1), respectively, significantly lowered the apoptotic rate of the cells compared with that of the scramble siRNA-transfected cells. Lastly, our data suggested that CHOP- and caspase-12-dependent pathways were involved in ER stress-mediated podocyte apoptosis and that Bcl-2 suppression was involved in CHOP-mediated apoptosis. Collectively, our results indicate for the first time that AOPPs trigger podocyte apoptosis through induction of ER stress, which might be regulated by NADPH oxidase-dependent ROS through RAGE, and that this apoptosis is mediated by three unfolded protein response pathways, the PERK, ATF6, and IRE1 pathways, and the mediators, CHOP and caspase-12.

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Albumin overload down-regulates integrin-β1 through reactive oxygen species-endoplasmic reticulum stress pathway in podocytes

Cited by 16 publications

References 30 publications

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress

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