Endoplasmic Reticulum Stress Predicts Clinical Response to Cyclosporine Treatment in Primary Membranous Nephropathy

Jiang, Tao; Zhang, Wei; Wen, Yubing; Sun, Yu; Chen, Limeng; Li, Hang; Li, Mingxi; Li, Xuewang; Lafayette, Richard A.; Li, Xuemei

doi:10.1159/000446293

Cited by 14 publications

(6 citation statements)

References 34 publications

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“…Intact ER function is important for proteostasis in podocytes 14 , including production of components of the slitdiaphragm, adhesion complexes, and glomerular basement membrane (GBM) 13 . Protein misfolding in the ER (ER stress) contributes to the pathogenesis of human glomerular diseases 15 , in particular membranous nephropathy 16 , focal segmental glomerulosclerosis (FSGS) 17 , and diabetic nephropathy 18 . In podocytes, deletion of key autophagy genes leads to injury, implying that autophagy is important for proteostasis 19,20 .…”

Section: Introductionmentioning

confidence: 99%

Role of IRE1α in podocyte proteostasis and mitochondrial health

et al. 2020

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Glomerular epithelial cell (GEC)/podocyte proteostasis is dysregulated in glomerular diseases. The unfolded protein response (UPR) is an adaptive pathway in the endoplasmic reticulum (ER) that upregulates proteostasis resources. This study characterizes mechanisms by which inositol requiring enzyme-1α (IRE1α), a UPR transducer, regulates proteostasis in GECs. Mice with podocyte-specific deletion of IRE1α (IRE1α KO) were produced and nephrosis was induced with adriamycin. Compared with control, IRE1α KO mice had greater albuminuria. Adriamycin increased glomerular ER chaperones in control mice, but this upregulation was impaired in IRE1α KO mice. Likewise, autophagy was blunted in adriamycin-treated IRE1α KO animals, evidenced by reduced LC3-II and increased p62. Mitochondrial ultrastructure was markedly disrupted in podocytes of adriamycin-treated IRE1α KO mice. To pursue mechanistic studies, GECs were cultured from glomeruli of IRE1α flox/flox mice and IRE1α was deleted by Cre–lox recombination. In GECs incubated with tunicamycin, deletion of IRE1α attenuated upregulation of ER chaperones, LC3 lipidation, and LC3 transcription, compared with control GECs. Deletion of IRE1α decreased maximal and ATP-linked oxygen consumption, as well as mitochondrial membrane potential. In summary, stress-induced chaperone production, autophagy, and mitochondrial health are compromised by deletion of IRE1α. The IRE1α pathway is cytoprotective in glomerular disease associated with podocyte injury and ER stress.

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Section: Introductionmentioning

confidence: 99%

Role of IRE1α in podocyte proteostasis and mitochondrial health

et al. 2020

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“…To evaluate glomerulosclerosis and tubular atrophy, the parts were stained with hematoxylin and eosin (H&E) and periodic acid silver methenamine (PASM), respectively, and Masson-trichrome Goldner's to measure interstitial fibrosis. The diagnosis procedures were performed according to the renal pathology laboratory's standard protocols, as reported previously [14]. Two qualified neuropathologists with 15 years and 18 years of experience, respectively, conductedd pathologic diagnoses according to the Banff 2015 scheme [15] without referring to functional MRI results.…”

Section: Histopathological Analysismentioning

confidence: 99%

Assessment of chronic allograft injury in renal transplantation using diffusional kurtosis imaging

Zheng

Wang

et al. 2021

BMC Med Imaging

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Background Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. Methods Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m2) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30–60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI. Results With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = − 0.49, − 0.44, − 0.57, − 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis. Conclusion The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.

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“…The sections were stained in a routine manner, with hematoxylin and eosin (H&E) and periodic acid silver methenamine (PASM), to assess glomerulosclerosis and tubular atrophy, respectively, and with Masson-Goldner's trichrome to quantify interstitial brosis. The diagnosis procedures were performed according to the standard protocols of the renal pathology laboratory, as reported previously [10]. Pathologic diagnoses were performed by two experienced neuropathologists with 15 years and 18 years of experience, respectively, according to the Banff 2015 scheme [11] without referring to functional MRI results.…”

Section: Histopathological Analysismentioning

confidence: 99%

Assessment of Chronic Allograft Injury in Renal Transplantation Using Diffusional Kurtosis Imaging

Zheng

Wang

et al. 2020

Preprint

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Background: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. Methods: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73m2) level, they were divided to 3 groups: group 1, eGFR≥60 (n=10); group 2, eGFR 30–60 (n=69); group 3, eGFR<30 (n=31). We performed DKI on a clinical 3T magnetic resonance imaging (MRI) system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic (ROC) curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI.Results: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, while MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P =0.039, P <0.001, P <0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r=-0.49, -0.44, -0.57, -0.57, respectively; P<0.001), while cortical and medullary MK are positively correlated with eGFR (r=0.42, 0.38; P<0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis.Conclusion: The DKI technique is related to eGFR as allograft injury progresses, and is expected to become a potential non-invasive method for evaluating CAI.

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Endoplasmic Reticulum Stress Predicts Clinical Response to Cyclosporine Treatment in Primary Membranous Nephropathy

Cited by 14 publications

References 34 publications

Role of IRE1α in podocyte proteostasis and mitochondrial health

Role of IRE1α in podocyte proteostasis and mitochondrial health

Assessment of chronic allograft injury in renal transplantation using diffusional kurtosis imaging

Assessment of Chronic Allograft Injury in Renal Transplantation Using Diffusional Kurtosis Imaging

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