scholarly journals Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

2020 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Han Zhou ◽  
Ocean Setia ◽  
Alan Dardik ◽  
Carlos Fernandez-Hernando ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Wnt Signaling ◽  
Renal Fibrosis ◽  
Regulatory Control ◽  
Acid Oxidation ◽  
Cell Homeostasis ◽  
Kidney Fibrosis ◽  
Knock Out ◽  
Mesenchymal Transition

AbstractEndothelial cells play a key role in the regulation of disease and other developmental processes. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells by autocrine effects or of neighboring cell types by paracrine effects, and in both cases contribute to organ fibrosis. However, regulatory control of endothelial cell homeostasis, is not well studied. Diabetes induced renal fibrosis in endothelial GR knock out mice (GRfl/fl;Tie 1 Cre; GRECKO) but not in control mice (GRfl/fl); hypercholesterolemia further enhanced severe renal fibrosis in diabetic GRECKO; Apoe−/− (DKO) but not in diabetic littermates (GRfl/fl; Apoe−/−). The fibrogenic phenotype in the kidneys of diabetic GRECKO and diabetic DKO were associated with aberrant cytokine and chemokine reprogramming. Canonical Wnt signaling was identified as new target for the action of endothelial GR. Wnt inhibiton improved kidney fibrosis by mitigating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transitions (EMT). Similarly, activation of fatty acid oxidation also suppressed kidney fibrosis. Conditioned media from endothelial cells from diabetic GRECKO stimulated Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic core molecule in diabetes.

scholarly journals Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Han Zhou ◽  
Ocean Setia ◽  
Bing Liu ◽  
Keizo Kanasaki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Glucocorticoid Receptor ◽  
Wnt Signaling ◽  
Renal Fibrosis ◽  
Regulatory Control ◽  
Acid Oxidation ◽  
Diabetic Mice ◽  
Cell Homeostasis ◽  
Mesenchymal Transition

AbstractEndothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes.

scholarly journals Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

2020 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Jinpeng Li ◽  
Yuta Takagaki ◽  
Munehiro Kitada ◽  
Julie E. Goodwin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Metabolic Reprogramming ◽  
Loss Of Function ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Renal Tubular ◽  
Defective Metabolism

Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain-of-function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis; while its loss-of-function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked-activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGFβ/Smad3-dependent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial cell SIRT3 is a fundamental regulator of defective metabolism-regulating health and disease processes in the kidney.

scholarly journals Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis

2020 ◽  
Vol 13 (635) ◽  
pp. eaaz2597 ◽  
Author(s):  
Sara Lovisa ◽  
Eliot Fletcher-Sananikone ◽  
Hikaru Sugimoto ◽  
Janine Hensel ◽  
Sharmistha Lahiri ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Genetic Ablation ◽  
Endothelial To Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of Twist1 (which encodes Twist) or Snai1 (which encodes Snail) in VE-cadherin+ or Tie1+ endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial cross-talk in the development of kidney fibrosis with a potential for therapeutic intervention.

scholarly journals Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lukas S. Tombor ◽  
David John ◽  
Simone F. Glaser ◽  
Guillermo Luxán ◽  
Elvira Forte ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Endothelial Cell Migration ◽  
Metabolic Adaptation ◽  
Endothelial Cell Proliferation ◽  
Mesenchymal Transition ◽  
Single Cell Rna Sequencing

AbstractEndothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network.

scholarly journals GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Kaela Drzewiecki ◽  
Jungmin Choi ◽  
Joseph Brancale ◽  
Michael A. Leney-Greene ◽  
Sinan Sari ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Portal Hypertension ◽  
Liver Disease ◽  
Endothelial Cell ◽  
Sequencing Analysis ◽  
Major Contributor ◽  
Liver Sinusoidal Endothelial Cells ◽  
Cell Homeostasis ◽  
Liver Endothelial Cell ◽  
Insight Into

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

scholarly journals Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases

2019 ◽  
Vol 99 (2) ◽  
pp. 1281-1324 ◽  
Author(s):  
Sonsoles Piera-Velazquez ◽  
Sergio A. Jimenez
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Transforming Growth Factor ◽  
Mesenchymal Cell ◽  
Human Diseases ◽  
Type I ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Complex Biological Process ◽  
Endothelial To Mesenchymal Transition

Numerous studies have demonstrated that endothelial cells are capable of undergoing endothelial to mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation. EndMT is a complex biological process in which endothelial cells adopt a mesenchymal phenotype displaying typical mesenchymal cell morphology and functions, including the acquisition of cellular motility and contractile properties. Endothelial cells undergoing EndMT lose the expression of endothelial cell-specific proteins such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and initiate the expression of mesenchymal cell-specific genes and the production of their encoded proteins including α-smooth muscle actin, extra domain A fibronectin, N-cadherin, vimentin, fibroblast specific protein-1, also known as S100A4 protein, and fibrillar type I and type III collagens. Transforming growth factor-β1 is considered the main EndMT inducer. However, EndMT involves numerous molecular and signaling pathways that are triggered and modulated by multiple and often redundant mechanisms depending on the specific cellular context and on the physiological or pathological status of the cells. EndMT participates in highly important embryonic development processes, as well as in the pathogenesis of numerous genetically determined and acquired human diseases including malignant, vascular, inflammatory, and fibrotic disorders. Despite intensive investigation, many aspects of EndMT remain to be elucidated. The identification of molecules and regulatory pathways involved in EndMT and the discovery of specific EndMT inhibitors should provide novel therapeutic approaches for various human disorders mediated by EndMT.

scholarly journals Podocyte Glucocorticoid Receptors Are Essential for Glomerular Endothelial Cell Homeostasis in Diabetes Mellitus

2021 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Han Zhou ◽  
Ocean Setia ◽  
Alan Dardik ◽  
Carlos Fernandez‐Hernando ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Diabetic Nephropathy ◽  
Fatty Acid ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Wnt Signaling ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Transforming Growth Factor

Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte‐specific glucocorticoid receptor knockout (GR PKO ) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GR PKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor‐βR1 and β‐catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin‐positive cells were found in the kidneys of diabetic GR PKO mice. Podocytes isolated from diabetic GR PKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GR PKO mice. The glomerular endothelium of diabetic GR PKO mice demonstrated the features of endothelial‐to‐mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α‐smooth muscle actin, transforming growth factor‐βR1 and β‐catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte–endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

scholarly journals Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 296 ◽  
Author(s):  
Tobias Kretschmer ◽  
Merle Schulze-Edinghausen ◽  
Eva-Maria Turnwald ◽  
Ruth Janoschek ◽  
Inga Bae-Gartz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adipose Tissue ◽  
Endothelial Cell ◽  
Maternal Obesity ◽  
Serum Levels ◽  
Tube Formation ◽  
Cell Homeostasis ◽  
Cell Markers ◽  
Protein Levels ◽  
Mother And Child

Obesity during pregnancy is a known health risk for mother and child. Since obesity is associated with increased inflammatory markers, our objectives were to determine interleukin-6 (IL-6) levels in obese mice and to examine the effect of IL-6 on placental endothelial cells. Placentas, blood, and adipose tissue of C57BL/6N mice, kept on high fat diet before and during pregnancy, were harvested at E15.5. Serum IL-6 levels were determined and endothelial cell markers and IL-6 expression were measured by qRT-PCR and western blot. Immunostaining was used to determine surface and length densities of fetal capillary profiles and placental endothelial cell homeostasis. Human placental vein endothelial cells were cultured and subjected to proliferation, apoptosis, senescence, and tube formation assays after stimulation with hyperIL-6. Placental endothelial cell markers were downregulated and the percentage of senescent endothelial cells was higher in the placental exchange zone of obese dams and placental vascularization was strongly reduced. Additionally, maternal IL-6 serum levels and IL-6 protein levels in adipose tissue were increased. Stimulation with hyperIL-6 provoked a dose dependent increase of senescence in cultured endothelial cells without any effects on proliferation or apoptosis. Diet-induced maternal obesity led to an IUGR phenotype accompanied by increased maternal IL-6 serum levels. In the placenta of obese dams, this may result in a disturbed endothelial cell homeostasis and impaired fetal vasculature. Cell culture experiments confirmed that IL-6 is capable of inducing endothelial cell senescence.

scholarly journals Matrix metalloproteinase 9 induces endothelial-mesenchymal transition via Notch activation in human kidney glomerular endothelial cells

2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Ye Zhao ◽  
Xi Qiao ◽  
Lihua Wang ◽  
Tian Kui Tan ◽  
Hong Zhao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Notch Signaling ◽  
Matrix Metalloproteinase 9 ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Glomerular Endothelial Cells ◽  
Metalloproteinase 9 ◽  
Endothelial Mesenchymal Transition ◽  
Tgf Β1

Abstract Background Endothelial-mesenchymal transition (EndoMT) is a major source of myofibroblast formation in kidney fibrosis. Our previous study showed a profibrotic role for matrix metalloproteinase 9 (MMP-9) in kidney fibrosis via induction of epithelial-mesenchymal transition (EMT). Inhibition of MMP-9 activity reduced kidney fibrosis in murine unilateral ureteral obstruction. This study investigated whether MMP-9 also plays a role in EndoMT in human glomerular endothelial cells. Results TGF-β1 (10 or 20 ng/ml) induced EndoMT in HKGECs as shown by morphological changes. In addition, VE-cadherin and CD31 were significantly downregulated, whereas α-SMA, vimentin, and N-cadherin were upregulated. RT-PCR revealed that Snail, a known inducer of EMT, was upregulated. The MMP inhibitor GM6001 abrogated TGF-β1-induced EndoMT. Zymography indicated that MMP-9 was also upregulated in TGF-β1-treated HKGECs. Recombinant MMP-9 (2 μg/ml) induced EndoMT in HKGECs via Notch signaling, as evidenced by increased formation of the Notch intracellular domain (NICD) and decreased Notch 1. Inhibition of MMP-9 activity by its inhibitor showed a dose-dependent response in preventing TGF-β1-induced α-SMA and NICD in HKGECs, whereas inhibition of Notch signaling by γ-secretase inhibitor (GSI) blocked rMMP-9-induced EndoMT. Conclusions Taken together, our results demonstrate that MMP-9 plays an important role in TGF-β1-induced EndoMT via upregulation of Notch signaling in HKGECs.

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