Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury

Mukherjee, Kamalika; Gu, Changkyu; Collins, Agnieszka; Mettlen, Marcel; Samelko, Beata; Altintas, Mehmet M.; Sudhini, Yashwanth Reddy; Wang, Xuexiang; Bouley, Richard; Brown, Dennis; Pedro, Bradley P.; Bane, Susan; Gupta, Vineet; Brinkkoetter, Paul T.; Hagmann, Henning; Reiser, Jochen; Sever, Sanja

doi:10.1038/s41467-022-30101-4

Cited by 11 publications

(9 citation statements)

References 72 publications

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“…Suicidal NET formation: a Chromatin decondensation is mediated by PAD4 and/or NE.b Nuclear envelope rupture is modulated by nuclear translocation of PKCα or CDK4/6 which mediate nuclear lamina disassembly (electron microscopy images of b1 well organized nuclear lamina, or b2 disassembled nuclear lamina[256]). c Rupture of the plasma membrane is achieved by disassembly of cortical cytoskeleton (c1, electron microscopy image of actin cortex[257]). (α, β) Representative confocal microscopy images of an untreated neutrophil (α) and a PMA-treated neutrophil with ruptured nuclear envelope and extracellular NETs in which nuclear DNA forms the backbone of NETs that are decorated with the disassembled lamin B (β), stainings of lamin B and DNA with fluorescent-labeled anti-lamin B1 and DAPI.…”

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confidence: 99%

Moonlighting chromatin: when DNA escapes nuclear control

et al. 2023

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Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable.

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confidence: 99%

Moonlighting chromatin: when DNA escapes nuclear control

et al. 2023

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“…A significant enrichment in the RHO GTPases signalling pathway was also discovered, which is relevant because the RHO GTPases are involved in cell signalling pathways that can lead to kidney inflammation and fibrosis [ 31 , 33 ]. The Rho family GTPases are molecular switches that play a central role in dynamically regulating the actin cytoskeleton, but also of cellular morphology, motility, adhesion, and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a proteomic signature coupled with the kidney failure risk equation in predicting end stage kidney disease in a chronic kidney disease cohort

Ramírez Medina,

Ali,

Baricevic-Jones

et al. 2024

Clin Proteom

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Background The early identification of patients at high-risk for end-stage renal disease (ESRD) is essential for providing optimal care and implementing targeted prevention strategies. While the Kidney Failure Risk Equation (KFRE) offers a more accurate prediction of ESRD risk compared to static eGFR-based thresholds, it does not provide insights into the patient-specific biological mechanisms that drive ESRD. This study focused on evaluating the effectiveness of KFRE in a UK-based advanced chronic kidney disease (CKD) cohort and investigating whether the integration of a proteomic signature could enhance 5-year ESRD prediction. Methods Using the Salford Kidney Study biobank, a UK-based prospective cohort of over 3000 non-dialysis CKD patients, 433 patients met our inclusion criteria: a minimum of four eGFR measurements over a two-year period and a linear eGFR trajectory. Plasma samples were obtained and analysed for novel proteomic signals using SWATH-Mass-Spectrometry. The 4-variable UK-calibrated KFRE was calculated for each patient based on their baseline clinical characteristics. Boruta machine learning algorithm was used for the selection of proteins most contributing to differentiation between patient groups. Logistic regression was employed for estimation of ESRD prediction by (1) proteomic features; (2) KFRE; and (3) proteomic features alongside KFRE. Results SWATH maps with 943 quantified proteins were generated and investigated in tandem with available clinical data to identify potential progression biomarkers. We identified a set of proteins (SPTA1, MYL6 and C6) that, when used alongside the 4-variable UK-KFRE, improved the prediction of 5-year risk of ESRD (AUC = 0.75 vs AUC = 0.70). Functional enrichment analysis revealed Rho GTPases and regulation of the actin cytoskeleton pathways to be statistically significant, inferring their role in kidney function and the pathogenesis of renal disease. Conclusions Proteins SPTA1, MYL6 and C6, when used alongside the 4-variable UK-KFRE achieve an improved performance when predicting a 5-year risk of ESRD. Specific pathways implicated in the pathogenesis of podocyte dysfunction were also identified, which could serve as potential therapeutic targets. The findings of our study carry implications for comprehending the involvement of the Rho family GTPases in the pathophysiology of kidney disease, advancing our understanding of the proteomic factors influencing susceptibility to renal damage.

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“…Genetic studies highlight the significance of actin-regulatory proteins and upstream signaling factors for the integrity of podocyte foot processes, emphasizing actin’s central role [ 20 ]. Dynein’s function in podocytes may be mediated by its role in the actin cytoskeleton [ 21 , 22 ]. Additionally, the presence of clathrin-coated vesicles in podocyte foot processes raises the possibility that endocytosis defects contribute to abnormal foot processes [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and molecular docking of endogenous active metabolites in diabetic kidney disease

Xie,

Wang,

Chen

et al. 2023

Renal Failure

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Objectives Network pharmacology and molecular docking were used to predict endogenous active metabolites with protective effects in diabetic kidney disease (DKD). Methods We utilized metabolomics to screen differentially expressed metabolites in kidney tissues of mice with type 2 DKD and predicted potential targets using relevant databases. The interaction network between endogenous active metabolites and target proteins was established by integrating differentially expressed metabolites and proteins associated with DKD identified through proteomics. Gene ontology (GO) and signaling pathway enrichment analysis were performed. The biological functions of the active candidate metabolites and their effects on downstream pathways were also verified. Results Metabolomics revealed 130 differentially expressed metabolites. Through co-expression network analysis coupled with the investigation of differentially expressed proteins in proteomics, 2-hydroxyphenylpropionylglycine (2-HPG) emerged as a key regulator of DKD. 2-HPG was found to modulate the progression of DKD by regulating the conformation and activity of synaptophysin 1 (SYNJ1), with a correlation coefficient of 0.974. In vivo experiments revealed that SYNJ1 expression was significantly downregulated in the Macroalbuminuria Group compared to the Control Group and negatively correlated with proteinuria ( r = −0.7137), indicating its important role in DKD progression. Immunofluorescence demonstrated that treatment with 2-HPG restores the expression of the foot process marker protein Wilms tumor-1 (WT-1) in podocytes injured by high glucose levels. Western blot and polymerase chain reaction support the involvement of SYNJ1 in this process. Conclusions This study demonstrated the significance of the 2-HPG/SYNJ1 signaling axis in safeguarding the foot process of podocytes in DKD.

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Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury

Cited by 11 publications

References 72 publications

Moonlighting chromatin: when DNA escapes nuclear control

Moonlighting chromatin: when DNA escapes nuclear control

Evaluation of a proteomic signature coupled with the kidney failure risk equation in predicting end stage kidney disease in a chronic kidney disease cohort

Network pharmacology and molecular docking of endogenous active metabolites in diabetic kidney disease

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