scholarly journals VDR/Atg3 Axis Regulates Slit Diaphragm to Tight Junction Transition via p62-mediated Autophagy Pathway in Diabetic Nephropathy

2021 ◽  
Author(s):  
Bin Wang ◽  
Jing-yi Qian ◽  
Tao-tao Tang ◽  
Li-lu Lin ◽  
Nan Yu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tight Junction ◽  
Diabetic Animal ◽  
Slit Diaphragm ◽  
Autophagic Flux ◽  
The Novel ◽  
Foot Process ◽  
Autophagy Pathway ◽  
And Function ◽  
Early Diabetic Nephropathy

Foot process effacement is an important feature of early diabetic nephropathy (DN) which is closely related to the development of albuminuria. Under certain nephrotic conditions, the integrity and function of the glomerular slit diaphragm (SD) structure were impaired and replaced by the tight junction (TJ) structure, resulting in so-called SD-TJ transition, which could partially explain the effacement of foot processes at the molecular level. However, the mechanism underlying the SD-TJ transition has not been described in DN. Here, we demonstrated that impaired autophagic flux blocked p62 mediated degradation of ZO-1 (TJ protein) and promoted podocytes injury via activation of caspase 3 and caspase 8. Interestingly, the expression of VDR in podocytes was decreased under diabetic condition which impaired autophagic flux through down-regulating Atg3. Of note, we also found that VDR abundance was negatively associated with impaired autophagic flux and SD-TJ transition in the glomeruli from human renal biopsy samples with DN. Furthermore, VDR activation improved autophagic flux and attenuated SD-TJ transition in the glomeruli of diabetic animal models. In conclusion, our data provided the novel insight that VDR/Atg3 axis deficiency resulted in SD-TJ transition and foot processes effacement via blocking p62-mediated autophagy pathway in DN.<br>

scholarly journals VDR/Atg3 Axis Regulates Slit Diaphragm to Tight Junction Transition via p62-mediated Autophagy Pathway in Diabetic Nephropathy

2021 ◽  
Author(s):  
Bin Wang ◽  
Jing-yi Qian ◽  
Tao-tao Tang ◽  
Li-lu Lin ◽  
Nan Yu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tight Junction ◽  
Diabetic Animal ◽  
Slit Diaphragm ◽  
Autophagic Flux ◽  
The Novel ◽  
Foot Process ◽  
Autophagy Pathway ◽  
And Function ◽  
Early Diabetic Nephropathy

Foot process effacement is an important feature of early diabetic nephropathy (DN) which is closely related to the development of albuminuria. Under certain nephrotic conditions, the integrity and function of the glomerular slit diaphragm (SD) structure were impaired and replaced by the tight junction (TJ) structure, resulting in so-called SD-TJ transition, which could partially explain the effacement of foot processes at the molecular level. However, the mechanism underlying the SD-TJ transition has not been described in DN. Here, we demonstrated that impaired autophagic flux blocked p62 mediated degradation of ZO-1 (TJ protein) and promoted podocytes injury via activation of caspase 3 and caspase 8. Interestingly, the expression of VDR in podocytes was decreased under diabetic condition which impaired autophagic flux through down-regulating Atg3. Of note, we also found that VDR abundance was negatively associated with impaired autophagic flux and SD-TJ transition in the glomeruli from human renal biopsy samples with DN. Furthermore, VDR activation improved autophagic flux and attenuated SD-TJ transition in the glomeruli of diabetic animal models. In conclusion, our data provided the novel insight that VDR/Atg3 axis deficiency resulted in SD-TJ transition and foot processes effacement via blocking p62-mediated autophagy pathway in DN.<br>

scholarly journals VDR/Atg3 axis regulates slit diaphragm to tight junction transition via p62-mediated autophagy pathway in diabetic nephropathy

Diabetes ◽  
2021 ◽  
pp. db210205
Author(s):  
Bin Wang ◽  
Jing-yi Qian ◽  
Tao-tao Tang ◽  
Li-lu Lin ◽  
Nan Yu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tight Junction ◽  
Slit Diaphragm ◽  
Autophagy Pathway

P0989VDR/ATG3 AXIS REGULATES SLIT DIAGRAM TO TIGHT JUNCTION TRANSITION VIA P62-MEDIATED AUTOPHAGY PATHWAY IN DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jingyi Qian ◽  
Bin Wang ◽  
Bicheng Liu
Keyword(s):  
Diabetic Nephropathy ◽  
Tight Junction ◽  
Degradation Pathway ◽  
Serum Starvation ◽  
Autophagic Flux ◽  
Vdr Gene ◽  
Podocyte Injury ◽  
Autophagy Pathway

Abstract Background and Aims Vitamin D receptor (VDR) loss, slit diagram (SD) to tight junction (TJ) transition and impaired autophagic flux contribute to podocyte injury in diabetic nephrology. This study aims to examine the effect and mechanism of VDR on autophagic flux and SD-TJ transition in diabetic nephropathy. Method Renal biopsy tissues from DN patients at stage IIa, IIb, III, IV and patients with minimal lesions were used to evaluate the expression of VDR, autophagic flux and SD-TJ transition glomeruli. In vitro, cultured podocytes were treated with serum starvation (SS), autophagic inhibitors (3-methyladenine 3-MA or chloroquine CQ) to determine the degradation pathway of TJ marker ZO-1. Meanwhile, db/db mice and STZ-induced rats were used to explore the therapeutic effect and mechanism of VDR agonist in diabetic nephropathy. Results SD-TJ transition between foot processes could be observed under electron microscopy in DN patients at all stages, whereas foot processes were separated by the filtration slit and appeared to be single cross-strands in the normal glomeruli. There was a trend of increasing expression of autophagic marker p62 and ZO-1 and the expression of p62 is positively correlated with the changes of ZO-1 in the glomeruli of DN patients. In vitro, inhibiting autophagy with 3-MA and CQ resulted in the accumulation of ZO-1 in cultured podocytes. In addition, Co-IP experiments further convinced the interaction between p62 and ZO-1, which was enhanced by the activation of autophagy. Podocytes apoptosis and the activity of caspase 3 and caspase 8 were significantly increased in the presence of 3-MA or CQ, while these effects were rescued by silencing p62. According to VDR gene expression data in GEO database, VDR expression was decreased in diabetic nephropathy patients compared with normal people. Knocking down VDR lowered the expression of atg3 and leaded to the blockage of autophagy, which could be reversed by over-expressing Atg3. Podocytes treated with high glucose resulted in the decrease of VDR and Atg3, impaired autophagic flux and aggravated podocytes injury. However, VDR agonist treatment partially reversed all the changes. In vivo, db/db mice and STZ-induced rats (DN animal models) exhibited SD-TJ transition, massive proteinuria, decreased expression of VDR and podocin and the increased accumulation of p62 and ZO-1, all of which could be partially reversed by VDR agonist. Conclusion VDR loss contributed to the impairment of autophagic flux and SD-TJ transition via down-regulation Atg3 in diabetic nephropathy. Here, we identified a new mechanism and evidence for VDR agonist to treat diabetic nephropathy.

scholarly journals The number of podocyte and slit diaphragm is decreased in experimental diabetic nephropathy

2006 ◽  
Vol 21 (2) ◽  
pp. 87-91 ◽  
Author(s):  
Mauro Masson Lerco ◽  
Célia Sperandéo Macedo ◽  
Reinaldo José Silva ◽  
Daniela de Oliveira Pinheiro ◽  
César Tadeu Spadella
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Diabetic Rats ◽  
Slit Diaphragm ◽  
Diabetic Rat ◽  
Severe Diabetes ◽  
Foot Process ◽  
The Right ◽  
Alloxan Injection

PURPOSE: To determine the number of podocyte, slit diaphragms, slit diaphragm extensions and GBM thickness in diabetic nephropathy. METHODS: Sixty "Rattus Wistar"of both sexes weighing 200-300g were divided in two experimental groups: normal group 10 animals, and alloxan diabetic rats - 50 animals. Alloxan was administered in a single IV dose of 42mg/kg body weight. Body weight, water and food intake, diuresis, and blood and urine glucose were determined in both groups before alloxan injection and two weeks, six and twelve months after alloxan injection. Proteinuria was measured at 12 months in both groups. After 12 months animals were sacrificed, and the right kidney processed for electron microscopy. RESULTS: Clear clinical and laboratory signs of severe diabetes were seen, in all alloxan-diabetic rats at all follow-up times. Glomerular basement membrane (GBM) thickening, podocyte number, and slit diaphragm number and extension were determined. GBM of all diabetic rats was significantly thicker (median=0.29µm; semi-interquartile range=0.065µm) than in the normal rats (0.23µm; 0.035µm). Diabetic rat podocyte number (8; 1), slit diaphragm number (4; 1), and slit diaphragm extension (0.021µm; 0.00435µm) were significantly lower than in normal rats (11; 1) and (7; 1.5), and (0.031µm; 0.0058µm). Diabetic rat proteinuria (0.060mg/24h; 0.037mg/24h) was higher than in normal rats (0.00185mg/24h; 0.00055mg/24h). CONCLUSION: Experimental diabetes is associated with significant (p<0.05) changes in podocyte foot process, slit number, slit diaphragm extension, and GBM thickness.

scholarly journals Sidt2 is a key protein in the autophagy-lysosomal degradation pathway and is essential for the maintenance of kidney structure and filtration function

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Meng-ya Geng ◽  
Lizhuo Wang ◽  
Ying-ying Song ◽  
Jing Gu ◽  
Xin Hu ◽  
...  
Keyword(s):  
Degradation Pathway ◽  
Normal Function ◽  
Mrna Levels ◽  
Kidney Structure ◽  
Protein Levels ◽  
Basement Membrane Thickening ◽  
Foot Process ◽  
Autophagy Pathway ◽  
Lysosomal Membrane Protein ◽  
And Function

AbstractThe regulation and homeostasis of autophagy are essential for maintaining organ morphology and function. As a lysosomal membrane protein, the effect of Sidt2 on kidney structure and renal autophagy is still unknown. In this study, we found that the kidneys of Sidt2−/− mice showed changes in basement membrane thickening, foot process fusion, and mitochondrial swelling, suggesting that the structure of the kidney was damaged. Increased urine protein at 24 h indicated that the kidney function was also damaged. At the same time, the absence of Sidt2 caused a decrease in the number of acidic lysosomes, a decrease in acid hydrolase activity and expression in the lysosome, and an increase of pH in the lysosome, suggesting that lysosomal function was impaired after Sidt2 deletion. The accumulation of autophagolysosomes, increased LC3-II and P62 protein levels, and decreased P62 mRNA levels indicated that the absence of the Sidt2 gene caused abnormal autophagy pathway flow. Chloroquine experiment, immunofluorescence autophagosome, and lysosome fusion assay, and Ad-mcherry-GFP-LC3B further indicated that, after Sidt2 deletion, the production of autophagosomes did not increase, but the fusion of autophagosomes and lysosomes and the degradation of autophagolysosomes were impaired. When incubating Sidt2−/− cells with the autophagy activator rapamycin, we found that it could activate autophagy, which manifested as an increase in autophagosomes, but it could not improve autophagolysosome degradation. Meanwhile, it further illustrated that the Sidt2 gene plays an important role in the smooth progress of autophagolysosome processes. In summary, the absence of the Sidt2 gene caused impaired lysosome function and a decreased number of acidic lysosomes, leading to formation and degradation disorders of the autophagolysosomes, which eventually manifested as abnormal kidney structure and function. Sidt2 is essential in maintaining the normal function of the lysosomes and the physiological stability of the kidneys.

scholarly journals Differences between diabetic and non-diabetic nephropathy patients in cardiac structure and function at the beginning of hemodialysis and their impact on the prediction of mortality

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199758
Author(s):  
Chao Tang ◽  
Han Ouyang ◽  
Jian Huang ◽  
Jing Zhu ◽  
Xiaosong Gu
Keyword(s):  
Diabetic Nephropathy ◽  
Diastolic Dysfunction ◽  
Peak Velocity ◽  
Structure And Function ◽  
Cardiac Valve ◽  
Cardiac Structure ◽  
Prediction Of Mortality ◽  
Cardiac Structure And Function ◽  
Lv Diastolic Dysfunction ◽  
And Function

Objectives To characterize differences in cardiac structure and function in hemodialysis (HD) patients with diabetic nephropathy (DN) and in those without using echocardiography and to determine their impact on the prediction of mortality using echocardiographic parameters. Methods Clinical, laboratory, and echocardiographic data were collected from patients commencing HD. Results Compared with those without DN, patients with DN had lower peak velocity of the early diastolic wave (e′), larger left atria, and higher peak early diastolic velocity (E)/e′ and peak velocity of tricuspid regurgitation (TR). In addition, a larger proportion of DN patients had a combination of left ventricular (LV) diastolic dysfunction, cardiac valve calcification, moderate-to-severe cardiac valve regurgitation (CVR), and at least moderate pericardial effusion (PE). After accounting for age, sex, smoking, hypertension, hemoglobin, and albumin, DN was responsible for e′  < 10 cm/s, E/e′ >13 m/s, TR >2.8 m/s, LV diastolic dysfunction, CVR, and PE. LV diastolic dysfunction and E/e′ >13 were the most useful predictors of mortality in patients with DN. Conclusions Patients with DN who undergo HD tend to have worse LV diastolic function and are more likely to have heart valve problems. LV diastolic dysfunction and E/e′ are predictors of death in DN patients.

scholarly journals The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

2021 ◽  
Vol 22 (15) ◽  
pp. 7923
Author(s):  
Santiago Alvarez-Argote ◽  
Caitlin C. O’Meara
Keyword(s):  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Normal Function ◽  
Cardiac Conduction ◽  
Cell Detection ◽  
Fate Mapping ◽  
The Novel ◽  
Functional Roles ◽  
Macrophage Populations ◽  
And Function

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

scholarly journals Surgical procedures suppress autophagic flux in the kidney

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Carolyn N. Brown ◽  
Daniel Atwood ◽  
Deepak Pokhrel ◽  
Sara J. Holditch ◽  
Christopher Altmann ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Compensatory Hypertrophy ◽  
Autophagic Flux ◽  
Bafilomycin A1 ◽  
Concomitant Increase ◽  
Sham Surgery ◽  
And Function ◽  
Pro Inflammatory Cytokines

AbstractMany surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy. Genes associated with lysosomal biogenesis and function were decreased in sham surgery and UNX kidneys. In both sham surgery and UNX, there was suppressed autophagic flux in the kidney as indicated by the lack of an increase in LC3-II or autophagosomes seen on immunoblot, IF and EM after bafilomycin A1 administration and a concomitant increase in p62, a marker of autophagic cargo. There was a massive increase in pro-inflammatory cytokines, which are known to activate ERK1/2, in the serum after sham surgery and UNX. There was a large increase in ERK1/2 in sham surgery and UNX kidneys, which was blocked by the MEK1/2 inhibitor, trametinib. Trametinib also resulted in a significant decrease in p62. In summary, there was an intense systemic inflammatory response, an ERK-mediated increase in p62 and suppressed autophagic flux in the kidney after sham surgery and UNX. It is important that researchers are aware that changes in systemic pro-inflammatory cytokines, ERK1/2 and autophagy can be caused by sham surgery as well as the kidney injury/disease itself.

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