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Article ; Online: HK-2 cell response to TGF-β highly depends on cell culture medium formulations.

Garmaa, Gantsetseg / Manzéger, Anna / Haghighi, Samaneh / Kökény, Gábor

2023 Volume 161, Issue 1, Page(s) 69–79

Abstract: The immortalized human renal proximal tubular epithelial cell line HK-2 is most commonly used to study renal cell physiology and human kidney diseases with tubulointerstitial fibrosis such as diabetic nephropathy, obstructive uropathy or allograft ... ...

Abstract	The immortalized human renal proximal tubular epithelial cell line HK-2 is most commonly used to study renal cell physiology and human kidney diseases with tubulointerstitial fibrosis such as diabetic nephropathy, obstructive uropathy or allograft fibrosis. Epithelial-to-mesenchymal transition (EMT) is the main pathological process of tubulointerstitial fibrosis in vitro. Transforming growth factor-beta (TGF-β) is a key inducer of EMT. Several pro-fibrotic gene expression differences have been observed in a TGF-β-induced EMT model of HK-2 cells. However, growth conditions and medium formulations might greatly impact these differences. We investigated gene and protein expression of HK-2 cells cultured in six medium formulations. TGF-β1 increased the expression of ACTA2, TGFB1, COL4A1, EGR2, VIM and CTGF genes while reducing PPARG in all medium formulations. Interestingly, TGF-β1 treatment either increased or decreased EGR1, FN, IL6 and C3 gene expression, depending on medium formulations. The cell morphology was slightly affected, but immunoblots revealed TGFB1 and vimentin protein overexpression in all media. However, fibronectin expression as well as the nuclear translocation of EGR1 was medium dependent. In conclusion, our study demonstrates that, using the HK-2 in vitro model of EMT, the meticulous selection of appropriate cell culture medium formulation is essential to achieve reliable scientific results.
MeSH term(s)	Humans ; Transforming Growth Factor beta1/metabolism ; Transforming Growth Factor beta/metabolism ; Epithelial-Mesenchymal Transition ; Diabetic Nephropathies/metabolism ; Fibrosis ; Cell Culture Techniques ; Epithelial Cells/metabolism
Chemical Substances	Transforming Growth Factor beta1 ; Transforming Growth Factor beta
Language	English
Publishing date	2023-09-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1222930-1
ISSN	1432-119X ; 0301-5564 ; 0948-6143
ISSN (online)	1432-119X
ISSN	0301-5564 ; 0948-6143
DOI	10.1007/s00418-023-02237-x
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Article: Editorial: New Advances in Cardiorenal Syndrome.

Calvier, Laurent / Kökény, Gábor / Martinez-Martinez, Ernesto

Frontiers in cardiovascular medicine

2022 Volume 9, Page(s) 976846

Language	English
Publishing date	2022-07-14
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2022.976846
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Article ; Online: Pioglitazone Protects Tubular Epithelial Cells during Kidney Fibrosis by Attenuating miRNA Dysregulation and Autophagy Dysfunction Induced by TGF-β.

Manzéger, Anna / Garmaa, Gantsetseg / Mózes, Miklós M / Hansmann, Georg / Kökény, Gábor

International journal of molecular sciences

2023 Volume 24, Issue 21

Abstract: Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play an important role in the pathogenesis. We aimed to study the yet unknown effects of ... ...

Abstract	Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play an important role in the pathogenesis. We aimed to study the yet unknown effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (Pio) on renal autophagy and miRNA dysregulation during fibrosis. Mouse primary tubular epithelial cells (PTEC) were isolated, pre-treated with 5 µM pioglitazone, and then stimulated with 10 ng/mL TGF-β1 for 24 h. Male 10-week-old C57Bl6 control (CTL) and TGF-β overexpressing mice were fed with regular chow (TGF) or Pio-containing chow (20 mg/kg/day) for 5 weeks (TGF + Pio). PTEC and kidneys were evaluated for mRNA and protein expression. In PTEC, pioglitazone attenuated (
MeSH term(s)	Male ; Mice ; Animals ; Pioglitazone/pharmacology ; Transforming Growth Factor beta/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Kidney Diseases/drug therapy ; Kidney Diseases/etiology ; Kidney Diseases/metabolism ; Kidney/metabolism ; Transforming Growth Factor beta1/metabolism ; RNA, Messenger/genetics ; Fibrosis ; Autophagy ; Epithelial Cells/metabolism
Chemical Substances	Pioglitazone (X4OV71U42S) ; Transforming Growth Factor beta ; MicroRNAs ; Transforming Growth Factor beta1 ; RNA, Messenger
Language	English
Publishing date	2023-10-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242115520
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Article ; Online: PPARγ and TGFβ-Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys.

Kökény, Gábor / Calvier, Laurent / Hansmann, Georg

International journal of molecular sciences

2021 Volume 22, Issue 19

Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin ... ...

Abstract	Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.
MeSH term(s)	Animals ; Humans ; Kidney/metabolism ; Lung/metabolism ; PPAR gamma/agonists ; PPAR gamma/metabolism ; Pioglitazone/therapeutic use ; Pulmonary Arterial Hypertension/drug therapy ; Pulmonary Arterial Hypertension/metabolism ; Pulmonary Fibrosis/drug therapy ; Pulmonary Fibrosis/metabolism ; Renal Insufficiency/drug therapy ; Renal Insufficiency/metabolism ; Signal Transduction ; Transforming Growth Factor beta/metabolism
Chemical Substances	PPAR gamma ; PPARG protein, human ; Transforming Growth Factor beta ; Pioglitazone (X4OV71U42S)
Language	English
Publishing date	2021-09-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms221910431
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Article ; Online: Susceptibility to kidney fibrosis in mice is associated with early growth response-2 protein and tissue inhibitor of metalloproteinase-1 expression.

Kökény, Gábor / Németh, Ágnes / Kopp, Jeffrey B / Chen, Weiping / Oler, Andrew J / Manzéger, Anna / Rosivall, László / Mózes, Miklós M

Kidney international

2022 Volume 102, Issue 2, Page(s) 337–354

Abstract: Patients with chronic kidney disease and experimental animal models of kidney fibrosis manifest diverse progression rates. Genetic susceptibility may contribute to this diversity, but the causes remain largely unknown. We have previously described kidney ...

Abstract	Patients with chronic kidney disease and experimental animal models of kidney fibrosis manifest diverse progression rates. Genetic susceptibility may contribute to this diversity, but the causes remain largely unknown. We have previously described kidney fibrosis with a mild or severe phenotype in mice expressing transforming growth factor-beta1 (TGF-β1) under the control of a mouse albumin promoter (Alb/TGF-β1), on a mixed genetic background with CBAxC57Bl6 mice. Here, we aimed to examine how genetic background may influence kidney fibrosis in TGF-β1 transgenic mice, and in the unilateral ureteral obstruction (UUO) and subtotal nephrectomy (SNX) mouse models. Congenic C57Bl6(B6)-TGFβ and CBAxB6-TGFβ (F1) transgenic mice were generated and survival, proteinuria, kidney histology, transcriptome and protein expressions were analyzed. We investigated the kidneys of B6 and CBA mice subjected to UUO and SNX, and the effects of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) neutralization on the fibrotic process. CBAxB6-TGFβ mice developed severe kidney fibrosis and premature death, while B6-TGF-β mice had mild fibrosis and prolonged survival. Kidney early growth response factor-2 (EGR2) and TIMP-1 expression were induced only in CBAxB6-TGFβ mice. Similar strain-dependent early changes in EGR2 and TIMP-1 of mice subjected to UUO or SNX were observed. TIMP-1 neutralization in vivo hindered fibrosis both in transgenic mice and the SNX model. EGR2 over-expression in cultured HEK293 cells induced TIMP-1 while EGR2 silencing hindered TGF-β induced TIMP-1 production in HK-2 cells and ureteral obstructed kidneys. Finally, EGR2 and TIMP1 was increased in human kidneys manifesting focal segmental glomerulosclerosis suggesting a correlation between animal studies and patient clinical settings. Thus, our observations demonstrate a strong relationship between genetic background and the progression of kidney fibrosis, which might involve early altered EGR2 and TIMP-1 response, but the relationship to patient genetics remains to be explored.
MeSH term(s)	Animals ; Early Growth Response Protein 2/genetics ; Fibrosis ; HEK293 Cells ; Humans ; Kidney/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Transgenic ; Renal Insufficiency, Chronic/complications ; Tissue Inhibitor of Metalloproteinase-1/genetics ; Tissue Inhibitor of Metalloproteinase-1/metabolism ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism ; Ureteral Obstruction/complications ; Ureteral Obstruction/genetics ; Ureteral Obstruction/metabolism
Chemical Substances	Early Growth Response Protein 2 ; Egr2 protein, mouse ; Timp1 protein, mouse ; Tissue Inhibitor of Metalloproteinase-1 ; Transforming Growth Factor beta1
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2022.03.029
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Zs.A 797: Show issues

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Article ; Online: Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19.

Kökény, Gábor / Bakos, Tamás / Barta, Bálint András / Nagy, Georgina Viktória / Mészáros, Tamás / Kozma, Gergely T / Szabó, András / Szebeni, János / Merkely, Béla / Radovits, Tamás

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this ... ...

Abstract	Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3-4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions.
MeSH term(s)	Swine ; Animals ; Cytokines/metabolism ; Zymosan/pharmacology ; Interleukin-6/metabolism ; COVID-19 ; Cytokine Release Syndrome/etiology ; Leukocytes, Mononuclear/metabolism ; Immunity, Innate
Chemical Substances	Cytokines ; Zymosan (9010-72-4) ; Interleukin-6
Language	English
Publishing date	2023-01-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24021138
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Article ; Online: The PPARγ agonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3.

Németh, Ágnes / Mózes, Miklós M / Calvier, Laurent / Hansmann, Georg / Kökény, Gábor

BMC nephrology

2019 Volume 20, Issue 1, Page(s) 245

Abstract: Background: It has been proposed that peroxisome proliferator-activated receptor-γ (PPARγ) agonists might reduce renal fibrosis, however, several studies had contradictory results. Moreover, the possible interaction of TGF-β: Methods: Male C57Bl/6 J ... ...

Abstract	Background: It has been proposed that peroxisome proliferator-activated receptor-γ (PPARγ) agonists might reduce renal fibrosis, however, several studies had contradictory results. Moreover, the possible interaction of TGF-β Methods: Male C57Bl/6 J mice (control, CTL, n = 14) and TGF-β overexpressing transgenic mice (TGFβ, n = 14, having elevated plasma TGF-β Results: TGF-β Conclusions: Oral administration of PPARγ agonist pioglitazone significantly reduces TGF-β
MeSH term(s)	Animals ; Early Growth Response Protein 1/antagonists & inhibitors ; Early Growth Response Protein 1/metabolism ; Fibrosis ; Kidney Diseases/chemically induced ; Kidney Diseases/metabolism ; Kidney Diseases/prevention & control ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; PPAR gamma/agonists ; Pioglitazone/pharmacology ; Pioglitazone/therapeutic use ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/metabolism ; Transforming Growth Factor beta/antagonists & inhibitors ; Transforming Growth Factor beta/toxicity
Chemical Substances	Early Growth Response Protein 1 ; Egr1 protein, mouse ; PPAR gamma ; STAT3 Transcription Factor ; Stat3 protein, mouse ; Transforming Growth Factor beta ; Pioglitazone (X4OV71U42S)
Language	English
Publishing date	2019-07-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041348-8
ISSN	1471-2369 ; 1471-2369
ISSN (online)	1471-2369
ISSN	1471-2369
DOI	10.1186/s12882-019-1431-x
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Article ; Online: PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis.

Kökény, Gábor / Calvier, Laurent / Legchenko, Ekaterina / Chouvarine, Philippe / Mózes, Miklós M / Hansmann, Georg

Current opinion in nephrology and hypertension

2019 Volume 29, Issue 2, Page(s) 171–179

Abstract: Purpose of review: Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and apoptosis, pulmonary arterial smooth muscle cell (PASMC) proliferation, inflammation, vasoconstriction, and metabolic ...

Abstract	Purpose of review: Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and apoptosis, pulmonary arterial smooth muscle cell (PASMC) proliferation, inflammation, vasoconstriction, and metabolic disturbances that include disrupted bone morphogenetic protein receptor (BMPR2)-peroxisome proliferator-activated receptor gamma (PPARγ) axis and DNA damage. Activation of PPARγ improves many of these mechanisms, although erroneous reports on potential adverse effects of thiazolidinedione (TZD)-class PPARγ agonists reduced their clinical use in the past decade. Here, we review recent findings in heart, lung, and kidney research related to the pathobiology of vascular remodeling and tissue fibrosis, and also potential therapeutic effects of the PPARγ agonist pioglitazone. Recent findings: Independent of its metabolic effects (improved insulin sensitivity and fatty acid handling), PPARγ activation rescues BMPR2 dysfunction, inhibits TGFβ/Smad3/CTGF and TGFβ/pSTAT3/pFoxO1 pathways, and induces the PPARγ/apoE axis, inhibiting vascular remodeling. PPARγ activation dampens mtDNA damage via PPARγ/UBR5/ATM pathway, improves function of endothelial progenitor cells (EPCs), and decrease renal fibrosis by repressing TGFβ/pSTAT3 and TGFβ/EGR1. Summary: Pharmacological PPARγ activation improves many hallmarks of PAH, including dysfunction of BMPR2-PPARγ axis, PAEC, PASMC, EPC, mitochondria/metabolism, and inflammation. Recent randomized controlled trials, including IRIS (Insulin Resistance Intervention After Stroke Trial), emphasize the beneficial effects of PPARγ agonists in PAH patients, leading to recent revival for clinical use.
MeSH term(s)	Animals ; Bone Morphogenetic Protein Receptors, Type II/physiology ; DNA Damage ; Extracellular Matrix/physiology ; Fibrosis ; Homeostasis ; Humans ; Hypertension, Pulmonary/etiology ; Kidney/pathology ; Muscle, Smooth, Vascular/cytology ; Myocardium/pathology ; Myocytes, Smooth Muscle/physiology ; PPAR gamma/agonists ; PPAR gamma/physiology ; Pulmonary Fibrosis/etiology ; Transforming Growth Factor beta1/physiology
Chemical Substances	PPAR gamma ; Transforming Growth Factor beta1 ; BMPR2 protein, human (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30)
Language	English
Publishing date	2019-12-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1151092-4
ISSN	1473-6543 ; 1535-3842 ; 1062-4813 ; 1062-4821
ISSN (online)	1473-6543 ; 1535-3842
ISSN	1062-4813 ; 1062-4821
DOI	10.1097/MNH.0000000000000580
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Zs.A 3686: Show issues

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Article ; Online: Chronic TGF-β1 Signaling in Pulmonary Arterial Hypertension Induces Sustained Canonical Smad3 Pathways in Vascular Smooth Muscle Cells.

Calvier, Laurent / Chouvarine, Philippe / Legchenko, Ekaterina / Kokeny, Gabor / Mozes, Miklos M / Hansmann, Georg

American journal of respiratory cell and molecular biology

2019 Volume 61, Issue 1, Page(s) 121–123

MeSH term(s)	Animals ; Humans ; Male ; Mice, Transgenic ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/metabolism ; Pulmonary Arterial Hypertension/metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; Smad3 Protein/metabolism ; Transforming Growth Factor beta1/metabolism
Chemical Substances	Smad3 Protein ; Transforming Growth Factor beta1
Language	English
Publishing date	2019-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2018-0275LE
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Article ; Online: Sustained hyperosmolarity increses TGF-ß1 and Egr-1 expression in the rat renal medulla.

Mózes, Miklós M / Szoleczky, Petra / Rosivall, László / Kökény, Gábor

BMC nephrology

2017 Volume 18, Issue 1, Page(s) 209

Abstract: Background: Although TGF-ß and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been ... ...

Abstract	Background: Although TGF-ß and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ß and Egr-1 expression. Methods: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. Results: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-ß and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-ß and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-ß and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. Conclusion: We conclude that both TGF-ß and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components.
Language	English
Publishing date	2017-07-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2041348-8
ISSN	1471-2369 ; 1471-2369
ISSN (online)	1471-2369
ISSN	1471-2369
DOI	10.1186/s12882-017-0626-2
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