Tribulus terrestris L. protects glomerular endothelial cells via the miR155-H2AC6 interaction network in hypertensive renal injury

Abstract Background N6-Methyladenosine (m6A) modification has been implicated in many bioprocesses. However, its functions in diabetic nephropathy (DN) have not been determined. Here, we investigated the role of METTL14, a key component of the m6A methyltransferase complex, in DN. Methods The expression of METTL14 was detected in DN patients and human renal glomerular endothelial cells (HRGECs). In vitro and in vivo experiments were performed to explore the functions of METTL14 on high glocse-induced HRGECs and renal injury of DN mice. We also investigated whether METTL14 works by regulating α-klotho expression through m6A modification. Results METTL14 were highly expressed in kidneys of DN patients and high glocse-induced HRGECs both at the mRNA and protein level. Overexpression of METTL14 increased ROS, TNF-α and IL-6 levels and apoptosis in HRGECs. Conversely, METTL14 silence decreased the levels of ROS, TNF-α and IL-6 and cell apoptosis. We confirmed that METTL14 down-regulated α-klotho expression in an m6A-dependent manner. In addition, we also found that METTL14 aggravated renal injury and inflammation of db/db mice, which could partially rescued by α-klotho. Conclusion Our data revealed that METTL14 plays a vital role in high glucose-induced glomerular endothelial cells and diabetic nephropathy through m6A modification of α-klotho.

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SMAD3-dependent and -independent pathways in glomerular injury associated with experimental glomerulonephritis

AJP Renal Physiology ◽

10.1152/ajprenal.00406.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. F152-F162

Author(s):

Ayesha Ghayur ◽

Manreet Kaur Padwal ◽

Limin Liu ◽

Jing Zhang ◽

Peter J. Margetts

Keyword(s):

Endothelial Cells ◽

Basement Membrane ◽

Renal Injury ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Glomerular Injury ◽

Podocyte Injury ◽

Glomerular Endothelial Cells ◽

End Stage ◽

Cell Changes

Glomerulonephritis (GN) is a common cause of end-stage kidney disease and is characterized by glomerular inflammation, hematuria, proteinuria, and progressive renal dysfunction. Transforming growth factor (TGF)-β is involved in glomerulosclerosis and interstitial fibrosis. TGF-β activates multiple signaling pathways, including the canonical SMAD pathway. We evaluated the role of SMAD signaling in renal injury and proteinuria in a murine model of GN. SMAD3+/+ or SMAD3−/− mice received anti-glomerular basement membrane antibodies to induce GN. We confirmed previous reports that demonstrated that SMAD3 is an important mediator of glomerulosclerosis and renal interstitial fibrosis. Proteinuria was highly SMAD3 dependent. We found differential effects of SMAD3 deletion on podocytes and glomerular endothelial cells. GN led to podocyte injury, including foot process effacement and loss of podocyte-specific markers. Interestingly, these changes were not SMAD3 dependent. Furthermore, there were significant changes to glomerular endothelial cells, including loss of fenestrations, swelling, and basement membrane reduplication, which were SMAD3 dependent. Despite ongoing markers of podocyte injury in SMAD3−/− mice, proteinuria was transient. Renal injury in the setting of GN involves TGF-β and SMAD3 signaling. Cell populations within the glomerulus respond differently to SMAD3 deletion. Proteinuria correlated more with endothelial cell changes as opposed to podocyte injury in this model.

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Expression of IFN‐induced Transmembrane Protein 1 in Glomerular Endothelial Cells

Pediatrics International ◽

10.1111/ped.14579 ◽

2020 ◽

Author(s):

Shun Hashimoto ◽

Tadaatsu Imaizumi ◽

Shojiro Watanabe ◽

Tomomi Aizawa ◽

Koji Tsugawa ◽

...

Keyword(s):

Endothelial Cells ◽

Transmembrane Protein ◽

Glomerular Endothelial Cells

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Hypoxia-induced apoptosis in cultured glomerular endothelial cells: Involvement of mitochondrial pathways

Kidney International ◽

10.1046/j.1523-1755.2003.00301.x ◽

2003 ◽

Vol 64 (6) ◽

pp. 2020-2032 ◽

Cited By ~ 45

Author(s):

Tetsuhiro Tanaka ◽

Toshio Miyata ◽

Reiko Inagi ◽

Kiyoshi Kurokawa ◽

Stephen Adler ◽

...

Keyword(s):

Endothelial Cells ◽

Glomerular Endothelial Cells ◽

Induced Apoptosis

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Case for the Panel: Unusual Ultrastructural Association Between Erythrocytes and Glomerular Endothelial Cells in Patients with Membranoproliferative Glomerulonephritis

Ultrastructural Pathology ◽

10.3109/01913129609016326 ◽

1996 ◽

Vol 20 (3) ◽

pp. 285-290

Author(s):

Samir M. El-Shoura

Keyword(s):

Endothelial Cells ◽

Membranoproliferative Glomerulonephritis ◽

Glomerular Endothelial Cells

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Activation of general control nonderepressible 2 kinase protects human glomerular endothelial cells from harmful high-glucose-induced molecular pathways

International Urology and Nephrology ◽

10.1007/s11255-016-1377-x ◽

2016 ◽

Vol 48 (10) ◽

pp. 1731-1739 ◽

Cited By ~ 10

Author(s):

Theodoros Eleftheriadis ◽

Konstantina Tsogka ◽

Georgios Pissas ◽

Georgia Antoniadi ◽

Vassilios Liakopoulos ◽

...

Keyword(s):

Endothelial Cells ◽

High Glucose ◽

Molecular Pathways ◽

General Control ◽

Glomerular Endothelial Cells ◽

Human Glomerular Endothelial Cells

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PR3 and Elastase Alter PAR1 Signaling and Trigger vWF Release via a Calcium-Independent Mechanism from Glomerular Endothelial Cells

PLoS ONE ◽

10.1371/journal.pone.0043916 ◽

2012 ◽

Vol 7 (8) ◽

pp. e43916 ◽

Cited By ~ 10

Author(s):

Samantha P. Tull ◽

Anne Bevins ◽

Sahithi Jyothsna Kuravi ◽

Simon C. Satchell ◽

Bahjat Al-Ani ◽

...

Keyword(s):

Endothelial Cells ◽

Glomerular Endothelial Cells ◽

Independent Mechanism

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TRPV4-mediated Ca2+ influx is essential to glomerular endothelial inflammation in sepsis associated acute kidney injury

10.21203/rs.3.rs-1031344/v1 ◽

2021 ◽

Author(s):

Xia Wang ◽

Yinhua Wang ◽

Guo Zhou ◽

Yi Li ◽

Huanhuan Huo ◽

...

Keyword(s):

Acute Kidney Injury ◽

Endothelial Cells ◽

Cell Injury ◽

Cecal Ligation ◽

Kidney Injury ◽

Blood Perfusion ◽

High Morbidity ◽

Endothelial Inflammation ◽

Glomerular Endothelial Cells

Abstract Background Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of critical patients and is associated with high morbidity and mortality. The glomerular endothelial cell injury is the main characteristics during S-AKI. Ca2+ influx is a key step in the establishment of endothelial injury. Transient receptor vanilloid subtype 4 (TRPV4) ion channels are permeable to Ca2+ and are widely expressed in endothelial cells. However, the role of TRPV4 on glomerular endothelial inflammation in S-AKI has remained elusive. Methods Mouse glomerular endothelial cells (MRGEC) were used to test the molecular mechanism of TRPV4 on LPS-induced glomerular endothelial inflammation. The cecal-ligation-and-puncture (CLP) model was established by ligation of cecum with 4-0 suture and punctured with a 21-gauge needle. Then 0.2mL faeces was extruded from the puncture site to trigger peritoneal inflammation. Results In the present study, we found that blocking TRPV4 diminishes LPS-induced cytosolic Ca2+-elevations, which are essential for glomerular endothelial inflammation and barrier function. Furthermore, TRPV4 regulated LPS-induced phosphorylation and translocation of NF-κB and IRF-3 in mouse glomerular endothelial cells (MRGEC). Clamping intracellular Ca2+ mimics the LPS-induce response seen in the absence of TRPV4. In vivo, pharmacological blockade or knock down of TRPV4 reduced the inflammatory response of glomerular endothelial cells, inhibited translocation of NF-κB and IRF-3, increased survival rate and improved renal function in CLP-induced sepsis but without altering renal cortical blood perfusion. Conclusions Taken together, these results suggested that inhibition of TRPV4 ameliorates glomerular endothelial inflammation, kidney dysfunction, and increased mortality via mediating Ca2+ overload and NF-κB/IRF-3 activation. These discoveries may provide novel pharmacological strategies for the treatment of glomerular endothelial dysfunction and kidney injury during endotoxemia, sepsis, and other inflammatory diseases.

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