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 Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Proximal Tubular Epithelial Cells through miR-545-3p–TNFSF10

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1032
Author(s):  
Mei-Chuan Kuo ◽  
Wei-An Chang ◽  
Ling-Yu Wu ◽  
Yi-Chun Tsai ◽  
Ya-Ling Hsu
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Critical Process ◽  
Necrosis Factor

Hypoxia is regarded as one of the pathophysiologic mechanisms of kidney injury and further progression to kidney failure. Epithelial-to-mesenchymal transition (EMT) in kidney tubules is a critical process of kidney fibrosis. This study utilized transcriptome analysis to investigate hypoxia-induced EMT through microRNA (miRNA)-modulated EMT in proximal tubular epithelial cells (PTECs). RNA sequencing revealed eight miRNAs were upregulated and three miRNAs were downregulated in PTECs cultured under hypoxia compared with normoxia. Among the 11 miRNAs, miR-545-3p has the highest expression in PTECs exposed to hypoxia, and miR-545-3p suppressed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10) expression. Hypoxia induced EMT in PTECs through miR-545-3p–TNFSF10 modulation, and TNFSF10-attenuated EMT resulted from hypoxia or miR-545-3p mimic transfection. These findings provided new perceptions of the unique regulation of the miR-545-3p–TNFSF10 interaction and their potential therapeutic effect in kidney injury induced by hypoxia.

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 The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis

2020 ◽  
Vol 134 (21) ◽  
pp. 2873-2891
Author(s):  
Sarah W.Y. Lok ◽  
Wai Han Yiu ◽  
Hongyu Li ◽  
Rui Xue ◽  
Yixin Zou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tubules ◽  
Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition

Abstract Protease-activated receptor (PAR)-1 has emerged as a key profibrotic player in various organs including kidney. PAR-1 activation leads to deposition of extracellular matrix (ECM) proteins in the tubulointerstitium and induction of epithelial–mesenchymal transition (EMT) during renal fibrosis. We tested the anti-fibrotic potential of vorapaxar, a clinically approved PAR-1 antagonist for cardiovascular protection, in an experimental kidney fibrosis model of unilateral ureteral obstruction (UUO) and an AKI-to-chronic kidney disease (CKD) transition model of unilateral ischemia–reperfusion injury (UIRI), and dissected the underlying renoprotective mechanisms using rat tubular epithelial cells. PAR-1 is activated mostly in the renal tubules in both the UUO and UIRI models of renal fibrosis. Vorapaxar significantly reduced kidney injury and ameliorated morphologic changes in both models. Amelioration of kidney fibrosis was evident from down-regulation of fibronectin (Fn), collagen and α-smooth muscle actin (αSMA) in the injured kidney. Mechanistically, inhibition of PAR-1 inhibited MAPK ERK1/2 and transforming growth factor-β (TGF-β)-mediated Smad signaling, and suppressed oxidative stress, overexpression of pro-inflammatory cytokines and macrophage infiltration into the kidney. These beneficial effects were recapitulated in cultured tubular epithelial cells in which vorapaxar ameliorated thrombin- and hypoxia-induced TGF-β expression and ECM accumulation. In addition, vorapaxar mitigated capillary loss and the expression of adhesion molecules on the vascular endothelium during AKI-to-CKD transition. The PAR-1 antagonist vorapaxar protects against kidney fibrosis during UUO and UIRI. Its efficacy in human CKD in addition to CV protection warrants further investigation.

MO328ASYMPTOMATIC HYPERURICEMIA ACTS AS ANTIOXIDANT DURING ACUTE KIDNEY INJURY AND DISEASE*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Qiuyue Ma ◽  
Viviane Gnemmi ◽  
Anders Hans-Joachim ◽  
Stefanie Steiger
Keyword(s):  
Acute Kidney Injury ◽  
Fatty Acid ◽  
Epithelial Cells ◽  
Kidney Function ◽  
Metabolic Activity ◽  
Mitochondrial Biogenesis ◽  
Kidney Injury ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Tubular Injury

Abstract Background and Aims Acute kidney injury (AKI) and disease (AKD) are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function. While there is no doubt that crystalline uric acid (UA) causes acute and chronic UA nephropathy, urolithiasis and kidney stone disease, the pathogenesis of asymptomatic HU in AKI/AKD is incompletely understood. In animal studies, elevated serum UA levels may lead to endothelial dysfunction, renin-angiotensin system activation and oxidative stress. However, such models do not mimic human HU. To overcome this issue, we established a model of AKI/AKD with clinically relevant serum UA levels and hypothesized that asymptomatic HU improves the outcomes after AKI/AKD by restoring metabolic activity and mitochondrial biogenesis in macrophages and tubular epithelial cells. Method Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet enriched with inosine. Hyperuricemic mice (serum UA ≥7 mg/dL) and mice without HU (serum UA 4-5 mg/dL) underwent uninephrectomy followed by unilateral ischemia-reperfusion (IR) to induce AKI/AKD. Serum and kidneys were collected on day 3 and 14 after AKI/AKD, and kidney function, tubular injury, inflammation, mitochondrial dysfunction, metabolic activity (fatty acid oxidation) and macrophage infiltration were quantified using GFR measurement, immunohistochemistry, colorimetric assays, electron microscopy, RT-PCR and flow cytometry. Results We observed an increase in serum UA levels from 7 to 10 mg/dL in hyperuricemic mice on day 3 after IR-induced AKI/AKD that returned to 7 mg/dL after 14 days (Figure left). While there was no difference in GFR between hyperuricemic and mice without HU with AKI/AKD on day 3, we found an improved kidney function in hyperuricemic mice on day 14 (Figure middle). This was associated with significantly less tubular injury and inflammation as well as an increase in the number of infiltrating anti-inflammatory M2-like macrophages as compared to mice without HU. Intrarenal mRNA expression level of the pro-oxidant heme-oxygenase-1 was reduced in hyperuricemic mice. However, the expression of anti-oxidant enzymes (Nrf-1 and Sod) and metabolic genes associated with fatty acid oxidation (Cpt1, Pparg, and Pgc1b) significantly increased as compared to mice without HU 14 days after AKI/AKD. In addition, HU increased the number of phospho-Histone-3 and intact proximal tubules and restored tubular mitochondrial morphology as indicated by an increased mitochondrial aspect ratio (Figure right). Conclusion Our data imply that asymptomatic HU improves kidney outcomes after IR-induced AKI/AKD because HU attenuates tubular injury and inflammation. In addition, we found that HU enhances the metabolic activity and anti-inflammatory M2-like macrophage polarization as well as restores mitochondrial biogenesis in tubular epithelial cells, suggesting that HU acts as antioxidant by improving kidney recovery after AKI/AKD.

scholarly journals Epithelial Wntless (Wls) regulates postnatal alveologenesis

Development ◽  
2021 ◽  
Author(s):  
Yinshan Fang ◽  
Hongxia Shao ◽  
Qi Wu ◽  
Neng Chun Wong ◽  
Natalie Tsong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gas Exchange ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Alveolar Epithelium ◽  
Mesenchymal Cells ◽  
Collagen Deposition ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Alveolar Formation

Alveologenesis requires the coordinated modulation of the epithelial and mesenchymal compartments to generate mature alveolar saccules for efficient gas exchange. However, the molecular mechanisms underlying the epithelial-mesenchymal interaction during alveologenesis are poorly understood. Here, we report that Wnts produced by epithelial cells are critical for neonatal alveologenesis. Deletion of the Wnt chaperon protein Wntless homolog (Wls) disrupts alveolar formation, resulting in enlarged saccules in Sftpc-Cre/Nkx2.1-Cre; Wlsloxp/loxp mutants. Although commitment of the alveolar epithelium is unaffected, α-SMA+ mesenchymal cells persist in the alveoli accompanied by increased collagen deposition and mutants exhibit exacerbated fibrosis following bleomycin challenge. Notably, α-SMA+ cells include a significant number of endothelial cells resembling endothelial to mesenchymal transition (EndMT) which is also present in Ager-CreER; Wlsloxp/loxp mutants following early postnatal Wls deletion. These findings provide initial evidence that epithelial-derived Wnts are critical for the differentiation of the surrounding mesenchyme during early postnatal alveologenesis.

eEOC-mediated modulation of endothelial autophagy, senescence, and EnMT in murine diabetic nephropathy

2014 ◽  
Vol 307 (6) ◽  
pp. F686-F694 ◽  
Author(s):  
D. Patschan ◽  
K. Schwarze ◽  
E. Henze ◽  
J. U. Becker ◽  
S. Patschan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Microvascular Damage ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Endothelial To Mesenchymal Transition ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy is the most frequent single cause of end-stage renal disease in our society. Microvascular damage is a key event in diabetes-associated organ malfunction. Early endothelial outgrowth cells (eEOCs) act protective in murine acute kidney injury. The aim of the present study was to analyze consequences of eEOC treatment of murine diabetic nephropathy with special attention on endothelial-to-mesenchymal transdifferentiation, autophagy, senescence, and apoptosis. Male C57/Bl6N mice (8–12 wk old) were treated with streptozotocin for 5 consecutive days. Animals were injected with untreated or bone morphogenetic protein (BMP)-5-pretreated syngeneic murine eEOCs on days 2 and 5 after the last streptozotocin administration. Four, eight, and twelve weeks later, animals were analyzed for renal function, proteinuria, interstitial fibrosis, endothelial-to-mesenchymal transition, endothelial autophagy, and senescence. In addition, cultured mature murine endothelial cells were investigated for autophagy, senescence, and apoptosis in the presence of glycated collagen. Diabetes-associated renal dysfunction (4 and 8 wk) and proteinuria (8 wk) were partly preserved by systemic cell treatment. At 8 wk, antiproteinuric effects were even more pronounced after the injection of BMP-5-pretreated cells. The latter also decreased mesenchymal transdifferentiation of the endothelium. At 8 wk, intrarenal endothelial autophagy (BMP-5-treated cells) and senescence (native and BMP-5-treated cells) were reduced. Autophagy and senescence in/of cultured mature endothelial cells were dramatically reduced by eEOC supernatant (native and BMP-5). Endothelial apoptosis decreased after incubation with eEOC medium (native and BMP-5). eEOCs act protective in diabetic nephropathy, and such effects are significantly stimulated by BMP-5. The cells modulate endothelial senescence, autophagy, and apoptosis in a protective manner. Thus, the renal endothelium could serve as a therapeutic target in diabetes-associated kidney dysfunction.

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