1,25-(OH)2D3 ameliorates renal interstitial fibrosis in UUO rats through the AMPKα/mTOR pathway

Objective To investigate the effects of 1,25(OH)2D3 on renal fibrosis associated with the AMP-activated protein kinase (AMPK)α/mechanistic target of rapamycin (mTOR) signalling pathway in a rat model of unilateral ureteral obstruction (UUO). Methods A total of 54 male Sprague Dawley rats were randomly divided into three groups: sham-operation group, UUO group, and UUO plus calcitriol (3 ng/100 g) group. Renal tissue was excised for histological examination by immunohistochemistry and Western blot, and for gene expression analysis using real-time polymerase chain reaction. Results 1,25(OH)2D3 enhanced AMPKα levels, inhibited mTOR levels and slowed the development of interstitial fibrosis in kidney tissue. Compared with the UUO plus calcitriol group, UUO rats demonstrated more severe renal damage characterized by marked tubular atrophy, interstitial fibrosis and significant induction of fibrogenic transforming growth factor-β1 and increased extra-cellular matrix proteins (α-smooth muscle actin and collagen type III), and decreased E-cadherin. Conclusion Treatment with 1,25(OH)2D3 altered the AMPKα/mTOR signalling pathway to suppress excessive fibroblast activation observed in UUO rats. This may serve as a novel mechanism to ameliorate renal dysfunction and fibrotic lesions.

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Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway

Biochemical Journal ◽

10.1042/bcj20170272 ◽

2017 ◽

Vol 474 (16) ◽

pp. 2733-2747 ◽

Cited By ~ 15

Author(s):

Chunyang Du ◽

Tao Zhang ◽

Xia Xiao ◽

Yonghong Shi ◽

Huijun Duan ◽

...

Keyword(s):

Ureteral Obstruction ◽

Transforming Growth Factor ◽

Unilateral Ureteral Obstruction ◽

Mtor Pathway ◽

Signalling Pathway ◽

Specific Class ◽

Protease Activated Receptor 2 ◽

Epithelial Inflammation ◽

Mtor Signalling ◽

Mtor Signalling Pathway

Protease-activated receptor-2 (PAR2), which belongs to a specific class of the G-protein-coupled receptors, is central to several inflammation processes. However, the precise molecular mechanism involved remains undefined. Autophagy has been previously shown to affect inflammation. In the present study, we examine the effect of PAR2 on kidney tubular epithelial autophagy and on autophagy-related inflammation and reveal the underlying mechanism involved. Autophagic activity and levels of autophagic marker LC3 were examined in human kidney tubular epithelial cells with PAR2 knockdown or overexpression. We administered the mammalian target of rapamycin (mTOR) inhibitor (rapamycin) or activator (MHY1485) to investigate the function of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. We also used transforming growth factor-β1 (TGF-β1)-induced HK-2 cell inflammation models to investigate the role of PAR2-associated autophagy in kidney tubular epithelial inflammation. PAR2 antagonist and rapamycin were administered to mice after unilateral ureteral obstruction to detect the correlations between PAR2, autophagy, and inflammation. Our results show that PAR2 overexpression in HK-2 cells led to a greater reduction in autophagy via the PI3K/Akt/mTOR pathway activation and induces autophagy-related inflammation. Meanwhile, a knockdown of PAR2 via PAR2 RNAi transfection greatly increased autophagy and alleviated autophagy-associated inflammation. In unilateral ureteral obstruction (UUO) kidneys, PAR2 antagonist treatment greatly attenuated renal inflammation and interstitial injury by enhancing autophagy. Moreover, inhibition of mTOR, rapa, markedly increased autophagy and inhibited the UUO-induced inflammation. We conclude that PAR2 induces kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Our results are suggestive that PAR2 inhibition may play a role in the treatment of diseases with increased inflammatory responses in renal systems.

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Tubular overexpression of Gremlin in transgenic mice aggravates renal damage in diabetic nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00023.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. F559-F568 ◽

Cited By ~ 24

Author(s):

Vanessa Marchant ◽

Alejandra Droguett ◽

Graciela Valderrama ◽

M. Eugenia Burgos ◽

Daniel Carpio ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Renal Damage ◽

Transforming Growth Factor ◽

Mesangial Cells ◽

Interstitial Fibrosis ◽

Smooth Muscle Actin ◽

Periodic Acid ◽

Kidney Tissue ◽

Renal Tubules ◽

Periodic Acid Schiff

Diabetic nephropathy (DN) is currently a leading cause of end-stage renal failure worldwide. Gremlin was identified as a gene differentially expressed in mesangial cells exposed to high glucose and in experimental diabetic kidneys. We have described that Gremlin is highly expressed in biopsies from patients with diabetic nephropathy, predominantly in areas of tubulointerstitial fibrosis. In streptozotocin (STZ)-induced experimental diabetes, Gremlin deletion using Grem1 heterozygous knockout mice or by gene silencing, ameliorates renal damage. To study the in vivo role of Gremlin in renal damage, we developed a diabetic model induced by STZ in transgenic (TG) mice expressing human Gremlin in proximal tubular epithelial cells. The albuminuria/creatinuria ratio, determined at week 20 after treatment, was significantly increased in diabetic mice but with no significant differences between transgenic (TG/STZ) and wild-type mice (WT/STZ). To assess the level of renal damage, kidney tissue was analyzed by light microscopy (periodic acid-Schiff and Masson staining), electron microscopy, and quantitative PCR. TG/STZ mice had significantly greater thickening of the glomerular basement membrane, increased mesangial matrix, and podocytopenia vs. WT/STZ. At the tubulointerstitial level, TG/STZ showed increased cell infiltration and mild interstitial fibrosis. In addition, we observed a decreased expression of podocin and overexpression of monocyte chemoattractant protein-1 and fibrotic-related markers, including transforming growth factor-β1, Col1a1, and α-smooth muscle actin. Together, these results show that TG mice overexpressing Gremlin in renal tubules develop greater glomerular and tubulointerstitial injury in response to diabetic-mediated damage and support the involvement of Gremlin in diabetic nephropathy.

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Dexrazoxane Alleviated Doxorubicin-Induced Nephropathy in Rats

Pharmacology ◽

10.1159/000521220 ◽

2022 ◽

pp. 1-10

Author(s):

Huihui Hu ◽

Caipeng Xie ◽

Zeping Weng ◽

Pei Yu ◽

Yuqiang Wang ◽

...

Keyword(s):

Renal Function ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Smooth Muscle Actin ◽

Periodic Acid ◽

Kidney Tissue ◽

Tunel Staining ◽

Protective Effects ◽

Renal Interstitial Fibrosis ◽

Alpha Smooth Muscle Actin

Introduction: Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application of DOX is restricted by its multiple organ toxicity including nephrotoxicity. This study investigated the protective effects and mechanisms of dexrazoxane (DZR) against DOX-induced nephropathy in rats. Methods: Male Sprague Dawley rats received 2.5 mg/kg DOX once a week for 5 consecutive weeks. 24-h urinary protein and renal function injury biomarkers were determined to evaluate the renal function. Histopathological changes and glomerulosclerosis were examined by hematoxylin and eosin and periodic acid-Schiff staining. The change of renal ultrastructure in the DOX-induced rats was observed by the electron microscopy. The renal apoptosis was detected by TUNEL staining and measured the protein expression of Caspase-3, Bcl-2, and Bax. Renal interstitial fibrosis was determined by Masson staining and immunohistochemistry examination. The levels of vimentin, alpha-smooth muscle actin (α-SMA), and transforming growth factor β (TGF-β) in kidney tissue were detected by Western blot. Results: DZR pretreatment markedly raised the survival rate and improved the renal dysfunction in DOX-treated rats. DZR ameliorated DOX-induced histopathological lesion of glomerular and tubular and apoptosis. DZR restored the oxidant/antioxidant balance via regulating the levels of MDA, SOD, and TAC. DZR reduced DOX-induced collagen IV deposition and renal interstitial fibrosis and downregulated the fibrosis-related protein expressions of vimentin, α-SMA, and TGF-β1. Conclusion: Our results suggest DZR exerted its protective effects against DOX-induced nephropathy through inhibition of lipid peroxidation, apoptosis, and fibrosis.

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Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism

Molecular Autism ◽

10.1186/s13229-017-0182-4 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 31

Author(s):

Kit San Yeung ◽

Winnie Wan Yee Tso ◽

Janice Jing Kun Ip ◽

Christopher Chun Yu Mak ◽

Gordon Ka Chun Leung ◽

...

Keyword(s):

Developmental Delay ◽

Signalling Pathway ◽

Mtor Signalling ◽

Mtor Signalling Pathway

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PI3K/Akt/mTOR signalling pathway activation in patients with ER-positive, metachronous, contralateral breast cancer treated with hormone therapy

European Journal of Cancer ◽

10.1016/s0959-8049(18)30502-1 ◽

2018 ◽

Vol 92 ◽

pp. S91

Author(s):

H. Kanaizumi ◽

C. Higashi ◽

Y. Tanaka ◽

M. Hamada ◽

W. Shinzaki ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Therapy ◽

Contralateral Breast Cancer ◽

Contralateral Breast ◽

Signalling Pathway ◽

Pathway Activation ◽

Er Positive ◽

Mtor Signalling ◽

Mtor Signalling Pathway

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Insights into the PI3-K-PKB-mTOR signalling pathway from small molecules

Journal of Chemical Biology ◽

10.1007/s12154-008-0008-0 ◽

2008 ◽

Vol 1 (1-4) ◽

pp. 49-62 ◽

Cited By ~ 13

Author(s):

Richard M. Gunn ◽

Helen C. Hailes

Keyword(s):

Small Molecules ◽

Signalling Pathway ◽

Mtor Signalling ◽

Mtor Signalling Pathway

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Hnf1α is required for proper gut epithelial endocrine cell specification and controls the mTOR signalling pathway in mice

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1007.5 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Francois Boudreau ◽

Carine R Lussier ◽

Francois Brial ◽

Nathalie Rivard ◽

Nathalie Perreault

Keyword(s):

Endocrine Cell ◽

Signalling Pathway ◽

Cell Specification ◽

Mtor Signalling ◽

Mtor Signalling Pathway

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Automatic Evaluation of Histological Prognostic Factors Using Two Consecutive Convolutional Neural Networks on Kidney Samples

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.07830621 ◽

2021 ◽

pp. CJN.07830621

Author(s):

Elise Marechal ◽

Adrien Jaugey ◽

Georges Tarris ◽

Michel Paindavoine ◽

Jean Seibel ◽

...

Keyword(s):

Neural Networks ◽

Convolutional Neural Networks ◽

Interstitial Fibrosis ◽

Kidney Tissue ◽

Area Under The Curve ◽

Tubular Atrophy ◽

Prognostic Features ◽

Glomerular Volume ◽

Luminal Stenosis ◽

Histological Data

Background and Objectives: The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histological criteria. These criteria notably include glomerular density, glomerular volume, vascular luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a Deep Learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histological prognostic features. Design, setting, participants, and measurements: Two hundred and forty one samples of healthy kidney tissue were split into 3 independent cohorts. The "Training" cohort (n=65) was used to train two Convolutional Neural Networks: one to detect the cortex and a second one to segment the kidney structures. The "Test" cohort (n=50) assessed their performances by comparing manually outlined regions of interest to predicted ones. The "Application" cohort (n=126) compared prognostic histological data obtained manually or through the algorithm based on the combination of the two Convolutional Neural Networks. Results: In the Test cohort, the networks isolated the cortex and segmented the elements of interest with good performances (more than 90% of the cortex, healthy tubules, glomeruli, and even globally sclerotic glomeruli were detected). In the Application cohort, the expected and predicted prognostic data were significantly correlated. The correlation coefficients r were respectively 0.85 for glomerular volume, 0.51 for glomerular density, 0.75 for interstitial fibrosis, 0.71 for tubular atrophy, and 0.73 for vascular intimal thickness. The algorithm had a good ability to predict significant (> 25%) tubular atrophy and interstitial fibrosis level (ROC curve with an area under the curve 0.92 and 0.91, respectively) or a significant vascular luminal stenosis (> 50%) (area under the curve 0.85). Conclusion: This freely available tool enables the automated segmentation of kidney tissue to obtain prognostic histological data in a fast, objective, reliable and reproducible way.

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