The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes

Navarro-Betancourt, José R.; Papillon, Joan; Guillemette, Julie; Chung, Chen-Fang; Cybulsky, Andrey V.

doi:10.1016/j.bbadis.2022.166391

Cited by 10 publications

(23 citation statements)

References 72 publications

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“…This conclusion is based on mass spectrometry spectral counts, which are a semi-quantitative practical measure of protein abundance. The mean spectral counts of EGFR were 4.33 in untreated control GECs and 5.33 in KO GECs (3 measurements per group), reflecting low expression ( 13 ). HER2 spectral counts were not detected.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, while neratinib was identified due to its induction of ER/ UPR and autophagy gene signatures, it should be noted that the GECs used in this study express low levels of EGFR. This conclusion is based on mass spectrometry spectral counts, which are a semi-quantitative (3 measurements per group), reflecting low expression (13). HER2 spectral counts were not detected.…”

Section: Neratinib Reduces Gec Injurymentioning

confidence: 89%

“…For example, mice with podocyte-specific genetic deletion of IRE1α show reduced induction of ER chaperones and autophagy that is associated with podocyte injury as the mice age, and exacerbation of injury in experimental glomerulopathies. “Preconditioning” of animals to induce the UPR or treatment of animals with chemical chaperones to reduce ER protein misfolding attenuate glomerular disease ( 7 , 12 , 13 ). Mice with podocyte-specific deletion of the key autophagy mediators ATG5 or ATG7 show age-related podocyte injury and exaggerated injury in experimental glomerulopathies ( 7 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

Chung

Papillon²,

Navarro-Betancourt³

et al. 2023

Front. Med.

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BackgroundHuman glomerulonephritis (GN)—membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN), as well as diabetic nephropathy (DN) are leading causes of chronic kidney disease. In these glomerulopathies, distinct stimuli disrupt metabolic pathways in glomerular cells. Other pathways, including the endoplasmic reticulum (ER) unfolded protein response (UPR) and autophagy, are activated in parallel to attenuate cell injury or promote repair.MethodsWe used publicly available datasets to examine gene transcriptional pathways in glomeruli of human GN and DN and to identify drugs.ResultsWe demonstrate that there are many common genes upregulated in MN, FSGS, IgAN, and DN. Furthermore, these glomerulopathies were associated with increased expression of ER/UPR and autophagy genes, a significant number of which were shared. Several candidate drugs for treatment of glomerulopathies were identified by relating gene expression signatures of distinct drugs in cell culture with the ER/UPR and autophagy genes upregulated in the glomerulopathies (“connectivity mapping”). Using a glomerular cell culture assay that correlates with glomerular damage in vivo, we showed that one candidate drug – neratinib (an epidermal growth factor receptor inhibitor) is cytoprotective.ConclusionThe UPR and autophagy are activated in multiple types of glomerular injury. Connectivity mapping identified candidate drugs that shared common signatures with ER/UPR and autophagy genes upregulated in glomerulopathies, and one of these drugs attenuated injury of glomerular cells. The present study opens the possibility for modulating the UPR or autophagy pharmacologically as therapy for GN.

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Section: Resultsmentioning

confidence: 99%

Section: Neratinib Reduces Gec Injurymentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

Chung

Papillon²,

Navarro-Betancourt³

et al. 2023

Front. Med.

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“…In control incubations (performed in parallel), primary antibody was replaced with nonimmune IgG. In some experiments, cell nuclei were stained with Hoechst H33342 [32,33]. Glomeruli in experimental groups were selected randomly and images were acquired using a Zeiss Axio Observer Z1 LSM780 laser scanning confocal microscope with ZEN2010 software (McGill University Health Centre Research Institute Imaging Platform).…”

Section: Microscopymentioning

confidence: 99%

Genetic Deletion of Calcium-independent Phospholipase A₂γ Protects Mice from Diabetic Nephropathy

Cybulsky,

Papillon,

Guillemette

et al. 2024

Preprint

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Calcium-independent phospholipase A2γ (iPLA2γ) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis, deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy. Hyperglycemia was induced in male mice with streptozotocin (STZ). STZ induced progressive albuminuria in control mice (over 21 weeks), while albuminuria did not increase in iPLA2γ KO mice, remaining comparable to untreated groups. Despite similar exposure to STZ, the STZ-treated iPLA2γ KO mice developed a lower level of hyperglycemia compared to STZ-treated control. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even iPLA2γ KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in diabetic control mice. Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in diabetic control compared to diabetic iPLA2γ KO mice. Glomerular matrix was expanded in diabetic mice, with control exceeding iPLA2γ KO. Glomerular autophagy (increased LC3-II and decreased p62) was enhanced in diabetic iPLA2γ KO mice compared to control. Treatment of cultured GECs with H2O2 resulted in increased cell death in control GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with high glucose compared to low glucose. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. In conclusion, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This is associated with increased glomerular autophagy.

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“…In glomerular epithelial cells, RTN3L expression was upregulated after 2 h of tunicamycin treatment, and after 24 h showed increased colocalization with LC3. These responses were impaired by knockout of UPR transducer IRE1α, suggesting that RTN3L is under the transcription control of the IRE1α arm of the UPR (Navarro‐Betancourt et al, 2022).…”

Section: Membrane‐associated Receptorsmentioning

confidence: 99%

ER‐phagy in neurodegeneration

Hill

Sykes

Mellick

2023

J of Neuroscience Research

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There are many cellular mechanisms implicated in the initiation and progression of neurodegenerative disorders. However, age and the accumulation of unwanted cellular products are a common theme underlying many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Niemann–Pick type C. Autophagy has been studied extensively in these diseases and various genetic risk factors have implicated disruption in autophagy homoeostasis as a major pathogenic mechanism. Autophagy is essential in the maintenance of neuronal homeostasis, as their postmitotic nature makes them particularly susceptible to the damage caused by accumulation of defective or misfolded proteins, disease‐prone aggregates, and damaged organelles. Recently, autophagy of the endoplasmic reticulum (ER‐phagy) has been identified as a novel cellular mechanism for regulating ER morphology and response to cellular stress. As neurodegenerative diseases are generally precipitated by cellular stressors such as protein accumulation and environmental toxin exposure the role of ER‐phagy has begun to be investigated. In this review we discuss the current research in ER‐phagy and its involvement in neurodegenerative diseases.

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The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes

Cited by 10 publications

References 72 publications

Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

Genetic Deletion of Calcium-independent Phospholipase A₂γ Protects Mice from Diabetic Nephropathy

ER‐phagy in neurodegeneration

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The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes

Cited by 10 publications

References 72 publications

Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

Genetic Deletion of Calcium-independent Phospholipase A2γ Protects Mice from Diabetic Nephropathy

ER‐phagy in neurodegeneration

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Product

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Genetic Deletion of Calcium-independent Phospholipase A₂γ Protects Mice from Diabetic Nephropathy