scholarly journals Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takahisa Kawaguchi ◽  
Kazuhiro Hasegawa ◽  
Itaru Yasuda ◽  
Hirokazu Muraoka ◽  
Hiroyuki Umino ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Early Stage ◽  
Descriptive Analysis ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Early Diabetes ◽  
Cellular Hypertrophy ◽  
Normal Glucose ◽  
Parietal Epithelial Cells ◽  
Glucose Condition

AbstractDiabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

scholarly journals Involvement of R-cadherin in the early stage of glomerulogenesis.

1998 ◽  
Vol 9 (7) ◽  
pp. 1234-1241 ◽  
Author(s):  
S Goto ◽  
E Yaoita ◽  
H Matsunami ◽  
D Kondo ◽  
T Yamamoto ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Upper Limb ◽  
Immunofluorescence Microscopy ◽  
Early Stage ◽  
Capillary Loop ◽  
Tubular Cells ◽  
Glomerular Epithelial Cells ◽  
Ureteric Buds ◽  
Parietal Epithelial Cells ◽  
E Cadherin

The earliest commitment to the formation of glomeruli is recognizable in S-shaped bodies. Although cell-cell adhesion seems likely to play a crucial role in this process, how glomerular epithelial cells segregate from the other parts of the nephron is unknown. In this study, immunofluorescence microscopy and monoclonal antibodies specific for mouse R-, E-, P- and N-cadherins were used to examine which of these adhesion molecules are involved in glomerulogenesis of the mouse kidney. Weak R-cadherin staining was first found in the vesicle stage, becoming restricted to glomerular visceral epithelial cells (VEC) during the S-shaped body stage. The intensity of this staining became stronger in the capillary loop stage, whereas parietal epithelial cells (PEC) and tubular cells did not stain. In the maturing stage, VEC gradually lost their staining for R-cadherin. E-cadherin was detected in ureteric buds and the upper limb of S-shaped bodies. From the capillary loop to the maturing stage, anti-E-cadherin stained epithelial cells in all tubule segments, but no label was seen in VEC or PEC. P-cadherin was also stained in the ureteric buds and in the upper limb of S-shaped bodies. N-Cadherin was weakly stained in cells at the vesicle stage, but thereafter staining of N-cadherin was not detected at any stage of glomerular formation. Immunoelectron microscopy of differentiating VEC was performed using antibodies specific to alpha-catenin, which is associated with cadherin. Subsequently, immunogold particles identifying alpha-catenin were localized on junctions between primary processes of VEC. These findings indicate that R-cadherin is uniquely expressed in differentiating VEC, suggesting an important role in the early stages of glomerulogenesis.

ERM Complex, a Therapeutic Target for Vascular Leakage Induced by Diabetes

2021 ◽  
Vol 28 ◽  
Author(s):  
Olga Simó-Servat ◽  
Hugo Ramos ◽  
Patricia Bogdanov ◽  
Marta García-Ramírez ◽  
Jordi Huerta ◽  
...  
Keyword(s):  
High Glucose ◽  
Therapeutic Target ◽  
Vascular Leakage ◽  
Cell Permeability ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Erm Proteins ◽  
High Glucose Condition ◽  
Tnf Α ◽  
Glucose Condition

Background: Ezrin, radixin, and moesin (the ERM complex) interact directly with membrane proteins regulating their attachment to actin filaments. ERM protein activation modifies cytoskeleton organization and alters the endothelial barrier function, thus favoring vascular leakage. However, little is known regarding the role of ERM proteins in diabetic retinopathy (DR). Objective: This study aimed to examine whether overexpression of the ERM complex exists in db/db mice and its main regulating factors. Methods: 9 male db/db mice and 9 male db/+ aged 14 weeks were analyzed. ERM proteins were assessed by western blot and by immunohistochemistry. Vascular leakage was determined by the Evans blue method. To assess ERM regulation, HRECs were cultured in a medium containing 5.5 mM D-glucose (mimicking physiological conditions) and 25 mM D-glucose (mimicking hyperglycemia that occurs in diabetic patients). Moreover, treatment with TNF-α, IL-1β, or VEGF was added to a high glucose condition. The expression of ERM proteins was quantified by RT-PCR. Cell permeability was evaluated by measuring movements of FITC-dextran. Results: A significant increase of ERM in diabetic mice in comparison with non-diabetic mice was observed. A high glucose condition alone did not have any effect on ERM expression. However, TNF-α and IL-1β induced a significant increase in ERM proteins. Conclusion: The increase of ERM proteins induced by diabetes could be one of the mechanisms involved in vascular leakage and could be considered as a therapeutic target. Moreover, the upregulation of the ERM complex by diabetes is induced by inflammatory mediators rather than by high glucose itself.

scholarly journals MMP-10 is Increased in Early Stage Diabetic Kidney Disease and can be Reduced by Renin-Angiotensin System Blockade

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
José María Mora-Gutiérrez ◽  
José Antonio Rodríguez ◽  
María A. Fernández-Seara ◽  
Josune Orbe ◽  
Francisco Javier Escalada ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Renin Angiotensin System ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Angiotensin System ◽  
Diabetic Kidney ◽  
Renin Angiotensin

AbstractMatrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD.

scholarly journals Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age

2015 ◽  
Vol 309 (2) ◽  
pp. F164-F178 ◽  
Author(s):  
Sebastian S. Roeder ◽  
Ania Stefanska ◽  
Diana G. Eng ◽  
Natalya Kaverina ◽  
Maria W. Sunseri ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
De Novo ◽  
Descriptive Analysis ◽  
Advanced Age ◽  
Collagen Type Iv ◽  
Mural Cell ◽  
Mesenchymal Transition ◽  
Type Iv ◽  
Parietal Epithelial Cells

Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers α-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and β-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-β, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age.

scholarly journals High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Xietian Pan ◽  
Chengxiang Li ◽  
Haokao Gao
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Patients ◽  
High Glucose Condition ◽  
Normal Glucose ◽  
Cardioprotective Effects ◽  
Glucagon Like Peptide 1 ◽  
Glucose Condition

An increased vulnerability has been detected after ischemia/reperfusion injury in cardiomyocytes in diabetic patients. Glucagon-like peptide-1 (GLP-1) has been proven to have a notable cardioprotective effect in cardiomyocytes. However, in diabetic patients, the cardioprotective effects of GLP-1 are compromised, which is called GLP-1 resistance. β-arrestin is one of the two main downstream effectors of GLP-1 and β-arrestin signaling pathway exerts cardioprotective effects upon activation of GLP-1R. Our hypothesis is that the increased vulnerability of cardiomyocytes in diabetic patients is partly due to disruption of the β-arrestin signaling pathway. To test this, we analyzed cardiomyocyte viability and survival in high glucose and normal glucose condition after hypoxia/reoxygenation injury in vitro, additional GLP-1 was used to determine whether β-arrestin signaling pathway was involved. We also investigated the role of mitochondrial dysfunction in GLP-1 resistance. Our results showed that cardioprotective effects of GLP-1 were reduced in high glucose cultured H9C2 cells compared to normal glucose cultured H9C2, verifying the existence of GLP-1 resistance in high glucose cultured H9C2 cells. Further study suggested that β-arrestin plays a key role in GLP-1 resistance: β-arrestin expression is notably downregulated in high glucose condition and cardioprotective effects of GLP-1 can be diminished by downregulation of β-arrestin in normal glucose condition while upregulation of β-arrestin can restore cardioprotective effects of GLP-1 in high glucose condition. Then we explore how β-arrestin affects the cardioprotective effects of GLP-1 and found that β-arrestin exerts cardioprotective effects by improving mitochondria quality control via the PI3K/Akt signaling pathway. Thus, our study found out a new mechanism of GLP-1 resistance of cardiomyocytes in high glucose conditions that impaired β-arrestin expression, caused mitochondria dysfunction and eventually cell death. Our study provided a new perspective in treating myocardial ischemia/reperfusion injury in diabetic patients.

Prevalence, Correlates and Management of Hyperglycemia in Diabetic Non-critically Ill Patients at a Tertiary Care Center in Lebanon

2019 ◽  
Vol 15 (2) ◽  
pp. 133-140 ◽  
Author(s):  
Ghada El Khoury ◽  
Hanine Mansour ◽  
Wissam K. Kabbara ◽  
Nibal Chamoun ◽  
Nadim Atallah ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Care Center ◽  
Descriptive Analysis ◽  
Tertiary Care ◽  
Multivariable Analysis ◽  
Length Of Hospital Stay ◽  
Retrospective Chart Review ◽  
Diabetic Patients

Background: Diabetes Mellitus is a chronic metabolic disease that affects 387 million people around the world. Episodes of hyperglycemia in hospitalized diabetic patients are associated with poor clinical outcomes and increased morbidity and mortality. Therefore, prevention of hyperglycemia is critical to decrease the length of hospital stay and to reduce complications and readmissions. Objective: The study aims to examine the prevalence of hyperglycemia and assess the correlates and management of hyperglycemia in diabetic non-critically ill patients. Methods: The study was conducted on the medical wards of a tertiary care teaching hospital in Lebanon. A retrospective chart review was conducted from January 2014 until September 2015. Diabetic patients admitted to Internal Medicine floors were identified. Descriptive analysis was first carried out, followed by a multivariable analysis to study the correlates of hyperglycemia occurrence. Results: A total of 235 medical charts were reviewed. Seventy percent of participants suffered from hyperglycemia during their hospital stay. The identified significant positive correlates for inpatient hyperglycemia, were the use of insulin sliding scale alone (OR=16.438 ± 6.765-39.941, p=0.001) and the low frequency of glucose monitoring. Measuring glucose every 8 hours (OR= 3.583 ± 1.506-8.524, p=0.004) and/or every 12 hours (OR=7.647 ± 0.704-79.231, p=0.0095) was associated with hyperglycemia. The major factor perceived by nurses as a barrier to successful hyperglycemia management was the lack of knowledge about appropriate insulin use (87.5%). Conclusion: Considerable mismanagement of hyperglycemia in diabetic non-critically ill patients exists; indicating a compelling need for the development and implementation of protocol-driven insulin order forms a comprehensive education plan on the appropriate use of insulin.

Review of Various Tasks Performed in the Preprocessing Phase of a Diabetic Retinopathy Diagnosis System

2020 ◽  
Vol 16 (4) ◽  
pp. 397-426
Author(s):  
Muhammad Nadeem Ashraf ◽  
Muhammad Hussain ◽  
Zulfiqar Habib
Keyword(s):  
Diabetic Retinopathy ◽  
Blood Vessels ◽  
Early Stage ◽  
Spherical Shape ◽  
Cost Effective ◽  
Lesion Detection ◽  
Diabetic Patients ◽  
Cad System ◽  
Non Invasive ◽  
Optic Discs

Diabetic Retinopathy (DR) is a major cause of blindness in diabetic patients. The increasing population of diabetic patients and difficulty to diagnose it at an early stage are limiting the screening capabilities of manual diagnosis by ophthalmologists. Color fundus images are widely used to detect DR lesions due to their comfortable, cost-effective and non-invasive acquisition procedure. Computer Aided Diagnosis (CAD) of DR based on these images can assist ophthalmologists and help in saving many sight years of diabetic patients. In a CAD system, preprocessing is a crucial phase, which significantly affects its performance. Commonly used preprocessing operations are the enhancement of poor contrast, balancing the illumination imbalance due to the spherical shape of a retina, noise reduction, image resizing to support multi-resolution, color normalization, extraction of a field of view (FOV), etc. Also, the presence of blood vessels and optic discs makes the lesion detection more challenging because these two artifacts exhibit specific attributes, which are similar to those of DR lesions. Preprocessing operations can be broadly divided into three categories: 1) fixing the native defects, 2) segmentation of blood vessels, and 3) localization and segmentation of optic discs. This paper presents a review of the state-of-the-art preprocessing techniques related to three categories of operations, highlighting their significant aspects and limitations. The survey is concluded with the most effective preprocessing methods, which have been shown to improve the accuracy and efficiency of the CAD systems.

scholarly journals Super-resolution microscopy reveals that Na+/K+-ATPase signaling protects against glucose-induced apoptosis by deactivating Bad

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Kristoffer Bernhem ◽  
Jacopo M. Fontana ◽  
Daniel Svensson ◽  
Liang Zhang ◽  
Linnéa M. Nilsson ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Chronic Diseases ◽  
Kidney Diseases ◽  
Super Resolution ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Renal Epithelial Cells ◽  
Apoptotic Process ◽  
Induced Apoptosis ◽  
Super Resolution Microscopy

AbstractActivation of the apoptotic pathway is a major cause of progressive loss of function in chronic diseases such as neurodegenerative and diabetic kidney diseases. There is an unmet need for an anti-apoptotic drug that acts in the early stage of the apoptotic process. The multifunctional protein Na+,K+-ATPase has, in addition to its role as a transporter, a signaling function that is activated by its ligand, the cardiotonic steroid ouabain. Several lines of evidence suggest that sub-saturating concentrations of ouabain protect against apoptosis of renal epithelial cells, a common complication and major cause of death in diabetic patients. Here, we induced apoptosis in primary rat renal epithelial cells by exposing them to an elevated glucose concentration (20 mM) and visualized the early steps in the apoptotic process using super-resolution microscopy. Treatment with 10 nM ouabain interfered with the onset of the apoptotic process by inhibiting the activation of the BH3-only protein Bad and its translocation to mitochondria. This occurred before the pro-apoptotic protein Bax had been recruited to mitochondria. Two ouabain regulated and Akt activating Ca2+/calmodulin-dependent kinases were found to play an essential role in the ouabain anti-apoptotic effect. Our results set the stage for further exploration of ouabain as an anti-apoptotic drug in diabetic kidney disease as well as in other chronic diseases associated with excessive apoptosis.

scholarly journals Crocodile blood supplementation protects vascular function in diabetic mice

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chui Yiu Bamboo Chook ◽  
Francis M. Chen ◽  
Gary Tse ◽  
Fung Ping Leung ◽  
Wing Tak Wong
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Quantitative Polymerase Chain Reaction ◽  
Functional Study ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Gene Expressions ◽  
Inflammatory State ◽  
Crocodile Blood

Abstract Cardiovascular disease is a major cause of mortality in diabetic patients due to the heightened oxidative stress and pro-inflammatory state in vascular tissues. Effective approaches targeting cardiovascular health for diabetic patients are urgently needed. Crocodile blood, an emerging dietary supplement, was suggested to have anti-oxidative and anti-inflammatory effects in vitro, which have yet to be proven in animal models. This study thereby aimed to evaluate whether crocodile blood can protect vascular function in diabetic mice against oxidation and inflammation. Diabetic db/db mice and their counterparts db/m+ mice were treated daily with crocodile blood soluble fraction (CBSF) or vehicle via oral gavage for 4 weeks before their aortae were harvested for endothelium-dependent relaxation (EDR) quantification using wire myograph, which is a well-established functional study for vascular function indication. Organ culture experiments culturing mouse aortae from C57BL/6 J mice with or without IL-1β and CBSF were done to evaluate the direct effect of CBSF on endothelial function. Reactive oxygen species (ROS) levels in mouse aortae were assessed by dihydroethidium (DHE) staining with inflammatory markers in endothelial cells quantified by quantitative polymerase chain reaction (qPCR). CBSF significantly improved deteriorated EDR in db/db diabetic mice through both diet supplementation and direct culture, with suppression of ROS level in mouse aortae. CBSF also maintained EDR and reduced ROS levels in mouse aortae against the presence of pro-inflammatory IL-1β. Under the pro-inflammatory state induced by IL-1β, gene expressions of inflammatory cytokines were downregulated, while the protective transcripts UCP2 and SIRT6 were upregulated in endothelial cells. Our study suggests a novel beneficial effect of crocodile blood on vascular function in diabetic mice and that supplementation of diet with crocodile blood may act as a complementary approach to protect against vascular diseases through anti-oxidation and anti-inflammation in diabetic patients. Graphical abstract

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