Tumor necrosis factor-α inhibits renin gene expression

2002 ◽  
Vol 283 (5) ◽  
pp. R1046-R1051 ◽  
Author(s):  
Vladimir Todorov ◽  
Markus Müller ◽  
Frank Schweda ◽  
Armin Kurtz
Keyword(s):  
Gene Expression ◽  
Knockout Mice ◽  
Primary Cultures ◽  
Cellular Level ◽  
Renin Synthesis ◽  
Tnf Α ◽  
Renin Gene ◽  
Renin Mrna ◽  
Vascular Proliferation ◽  
Factor Α

Renin, produced in renal juxtaglomerular (JG) cells, is a fundamental regulator of blood pressure. Accumulating evidence suggests that cytokines may directly influence renin production in the JG cells. TNF-α, which is one of the key mediators in immunity and inflammation, is known to participate in the control of vascular proliferation and contraction and hence in the pathogenesis of cardiovascular diseases. Thus TNF-α may exert its effects on the cardiovascular system through modulation of renal renin synthesis. Therefore we have tested the effect of TNF-α on renin transcription in As4.1 cells, which represent transformed mouse JG cells, and in native mouse JG cells in culture. Renin gene expression was also determined in mice lacking the gene for TNF-α (TNF-α knockout mice). TNF-α inhibited renin gene expression via an inhibition of the transcriptional activity, targeting the proximal 4.1 kb of the renin promoter in As4.1 cells. TNF-α also attenuated forskolin-stimulated renin gene expression in primary cultures of mouse JG cells. Mice lacking the TNF-α gene had almost threefold higher basal renal renin mRNA abundance relative to the control strain. The general physiological regulation of renin expression by salt was not disturbed in TNF-α knockout mice. Our data suggest that TNF-α inhibits renin gene transcription at the cellular level and thus may act as a modulator of renin synthesis in (physio)pathological situations.

Aldosterone enhances renin gene expression in juxtaglomerular cells

2004 ◽  
Vol 286 (2) ◽  
pp. F349-F355 ◽  
Author(s):  
Jürgen Klar ◽  
Helga Vitzthum ◽  
Armin Kurtz
Keyword(s):  
Gene Expression ◽  
Primary Cultures ◽  
Cellular Level ◽  
Juxtaglomerular Cells ◽  
Mrna Levels ◽  
Renin Synthesis ◽  
Corticosteroid Hormones ◽  
Renin Gene ◽  
Renin Mrna ◽  
Mrna Half Life

The secretion and synthesis of renin as the key regulator of the renin-angiotensin-aldosterone system are directly controlled by ANG II in the sense of a negative feedback. Because we found that renal afferent arterioles including the juxtaglomerular portion express the mineralocorticoid receptor, we aimed to characterize a possible direct effect of aldosterone on renin synthesis and renin secretion at the level of renal juxtaglomerular cells. Aldosterone (100 nM) clearly enhanced renin mRNA levels in primary cultures of mouse juxtaglomerular cells prestimulated with isoproterenol (100 nM) but had no effect on the exocytosis of stored renin. Similarly, in the mouse juxtaglomerular cell line As4.1, aldosterone time and concentration dependently increased renin mRNA abundance and prorenin secretion up to 2.5-fold. Moreover, aldosterone potentiated cAMP-induced renin gene expression in As4.1 cells. The effect of aldosterone was inhibited by spironolactone and was mimicked by corticosteroid hormones but not by sex steroids. Aldosterone had no influence on basal renin promoter activity but increased the renin mRNA half-life about threefold. In summary, these data suggest that aldosterone exerts a direct positive effect on renin gene expression at the cellular level probably by stabilizing renin mRNA.

Acute hypoxia stimulates renin secretion and renin gene expression in vivo but not in vitro

1997 ◽  
Vol 272 (4) ◽  
pp. R1105-R1111 ◽  
Author(s):  
T. Ritthaler ◽  
K. Schricker ◽  
F. Kees ◽  
B. Kramer ◽  
A. Kurtz
Keyword(s):  
Gene Expression ◽  
Acute Hypoxia ◽  
Primary Cultures ◽  
Renin Secretion ◽  
Plasma Norepinephrine ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Renin Gene ◽  
Renin Mrna

This study aimed at examining the influence of acute hypoxia on renin secretion and renin gene expression in the kidney. To this end, male Sprague-Dawley rats were exposed to severe hypoxic stress (8% O2) or to carbon monoxide (0.1% CO) for 6 h, and plasma renin activity (PRA) and renal renin mRNA levels were determined. PRA values increased from 3 to 13 and 10 ng angiotensin I x h(-1) x ml(-1), and renin mRNA levels increased by 120 and 100% during hypoxia and CO, respectively. Lowering the PO2 from 150 to 20 or 7 mmHg in the gas atmosphere of primary cultures of renal juxtaglomerular cells had no influence on renin secretion and renin gene expression after 6 and 20 h. Our findings thus suggest that both arterial and venous hypoxia can be powerful stimulators of renin secretion and renin gene expression in vivo. Because renal denervation did not prevent stimulation of the renin system by hypoxia, the effect could be indirectly mediated via the baroreceptor-macula densa mechanism. Another potential mediator of the effect could be circulating catecholamines, since we found that plasma norepinephrine increased from 0.7 to 1.5 and 2.4 ng/ml and plasma epinephrine increased from 0.3 to 1.4 and 2.7 ng/ml during hypoxia and CO inhalation, respectively.

JG cell expression and partial regulation of a human renin genomic transgene driven by a minimal renin promoter

1999 ◽  
Vol 277 (4) ◽  
pp. F634-F642 ◽  
Author(s):  
Patrick L. Sinn ◽  
Xiaoji Zhang ◽  
Curt D. Sigmund
Keyword(s):  
Gene Expression ◽  
Systemic Circulation ◽  
Proximal Promoter ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Specific Expression ◽  
Renin Synthesis ◽  
Human Renin ◽  
Renin Gene ◽  
Renin Mrna ◽  
Cell Expression

In the kidney, renin gene expression is exquisitely localized to the juxtaglomerular (JG) cells lining the afferent arteriole, having the capacity to regulate renin synthesis in response to a variety of physiological cues. We investigated human renin gene expression in transgenic mice containing a genomic construct driven by 149 bp of its proximal promoter to elucidate whether this was sufficient to confer JG-specific expression. Whereas human renin mRNA was permissively expressed in most tissues, the transgene was expressed mainly in JG cells in the kidney. Active human renin and human prorenin were found in the systemic circulation at levels consistent with previous transgenic models. Remarkably, two lines displayed an appropriate upregulation of transgene mRNA in response to angiotensin-converting enzyme inhibition, and two lines exhibited a downregulation of transgene mRNA in response to subpressor and pressor doses of ANG II. Our results suggest that 149 bp of the human renin proximal promoter, in a context of a genomic construct, are sufficient to confer human renin expression in renal JG cells and at least some aspects of appropriate regulation.

Renin Gene Expression in Fetal Kidneys of Pregnancies Complicated by Twin-Twin Transfusion Syndrome

2001 ◽  
Vol 4 (2) ◽  
pp. 175-179 ◽  
Author(s):  
Mark D. Kilby ◽  
Craig Platt ◽  
Martin J. Whittle ◽  
Jill Oxley ◽  
George B.M. Lindop
Keyword(s):  
Gene Expression ◽  
Renal Cortex ◽  
Donor Kidney ◽  
Mortality And Morbidity ◽  
Renal Vasoconstriction ◽  
Unidirectional Flow ◽  
Renin Synthesis ◽  
Renin Gene ◽  
Renin Mrna ◽  
Fetal Urine

Twin-twin transfusion syndrome (TTTS) complicates one in five monochorionic pregnancies and is generally associated with high mortality and morbidity. One twin (the recipient) grows appropriately and has polyhydramnios while the other (the donor) may have a reduced growth velocity and severe oligohydramnios. The disparities in amniotic fluid volumes represent differences in fetal urine output. These differences occur secondary to hemodynamic changes, in which the vascular arrangement of placental anastomoses in TTTS leads to unidirectional flow from the donor to the recipient twin. A better understanding of the pathophysiology may contribute to improved management of this morbid condition. We studied three consecutive prospectively diagnosed stillborn twin pairs affected by early-onset TTTS. Renin gene expression was studied in sections of fetal kidneys with immunocytochemistry using a renin anti-serum and with in situ hybridization using riboprobes complementary to renin mRNA, and renin-secreting cells (RCC) were counted. The overall maturation of the renal cortex was assessed by the percentage of immature glomeruli. The donor twin kidneys were smaller than those of the recipients, but the maturation of the renal cortex was not significantly different (28.2% immature glomeruli in the donor and 24.4% in the recipient kidney). The donor kidney showed increased renin gene expression with hyperplastic juxtaglomerular apparatuses (JGAs) that contained excess RCCs (median 20.02 [25th–75th centiles, 5.4, 25.1 RCCs per 100 glomeruli]). In contrast, the recipient kidney was virtually devoid of these cells (0.04 [0, 0.36] RCCs per 100 glomeruli; P < 0.05). In the donor kidney, increased renin release may, by a local action, contribute to renal vasoconstriction and oliguria. Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may, by an endocrine action, suppress renin synthesis in the recipient kidney, thereby increasing renal blood flow and causing polyuria and polyhydramnios. These changes in the renal RAS could thus contribute to the pathogenesis of TTTS. The renal renin changes noted here may represent a contributory or compensating mechanism, the success of which may dictate the overall survival of the twin pregnancy and allow better understanding of the pathophysiology and perhaps therapy that may be employed in this condition.

scholarly journals Manifestation of lipopolysaccharide-induced tolerance in neuro-glial primary cultures of the rat afferent somatosensory system

2021 ◽  
Vol 70 (4) ◽  
pp. 429-444
Author(s):  
Franz Nürnberger ◽  
Stephan Leisengang ◽  
Daniela Ott ◽  
Jolanta Murgott ◽  
Rüdiger Gerstberger ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Nuclear Translocation ◽  
Mrna Level ◽  
Primary Cultures ◽  
Somatosensory System ◽  
Cellular Level ◽  
Microglial Cells ◽  
Substantia Gelatinosa ◽  
Tnf Α ◽  
Pre Treatment

Abstract Objective Bacterial lipopolysaccharide (LPS) may contribute to the manifestation of inflammatory pain within structures of the afferent somatosensory system. LPS can induce a state of refractoriness to its own effects termed LPS tolerance. We employed primary neuro-glial cultures from rat dorsal root ganglia (DRG) and the superficial dorsal horn (SDH) of the spinal cord, mainly including the substantia gelatinosa to establish and characterize a model of LPS tolerance within these structures. Methods Tolerance was induced by pre-treatment of both cultures with 1 µg/ml LPS for 18 h, followed by a short-term stimulation with a higher LPS dose (10 µg/ml for 2 h). Cultures treated with solvent were used as controls. Cells from DRG or SDH were investigated by means of RT-PCR (expression of inflammatory genes) and immunocytochemistry (translocation of inflammatory transcription factors into nuclei of cells from both cultures). Supernatants from both cultures were assayed for tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by highly sensitive bioassays. Results At the mRNA-level, pre-treatment with 1 µg/ml LPS caused reduced expression of TNF-α and enhanced IL-10/TNF-α expression ratios in both cultures upon subsequent stimulation with 10 µg/ml LPS, i.e. LPS tolerance. SDH cultures further showed reduced release of TNF-α into the supernatants and attenuated TNF-α immunoreactivity in microglial cells. In the state of LPS tolerance macrophages from DRG and microglial cells from SDH showed reduced LPS-induced nuclear translocation of the inflammatory transcription factors NFκB and NF-IL6. Nuclear immunoreactivity of the IL-6-activated transcription factor STAT3 was further reduced in neurons from DRG and astrocytes from SDH in LPS tolerant cultures. Conclusion A state of LPS tolerance can be induced in primary cultures from the afferent somatosensory system, which is characterized by a down-regulation of pro-inflammatory mediators. Thus, this model can be applied to study the effects of LPS tolerance at the cellular level, for example possible modifications of neuronal reactivity patterns upon inflammatory stimulation.

Decreased perfusion pressure modulates renin and ANG II type 1 receptor gene expression in the rat kidney

1993 ◽  
Vol 264 (4) ◽  
pp. R696-R702 ◽  
Author(s):  
A. Tufro-McReddie ◽  
R. L. Chevalier ◽  
A. D. Everett ◽  
R. A. Gomez
Keyword(s):  
Gene Expression ◽  
Aortic Coarctation ◽  
Perfusion Pressure ◽  
Receptor Gene ◽  
At1 Receptor ◽  
Northern Analysis ◽  
Renin Gene ◽  
Renin Mrna ◽  
Receptor Gene Expression

To determine whether decreased perfusion pressure affects the abundance and distribution of renin and its mRNA and the expression of the angiotensin II type 1 (AT1) receptor gene within the kidney, adult male Sprague-Dawley rats were subjected to aortic coarctation proximal to the renal arteries (Coarc, n = 8) and compared with sham-operated rats (Sham, n = 6). Renal renin distribution was determined by immunocytochemistry using a specific polyclonal antibody against rat renin. Renin mRNA was assessed by in situ hybridization to a 35S-labeled oligonucleotide complementary to rat renin mRNA. Kidney AT1 mRNA levels were determined by Northern analysis using a 1,133-base pair rat AT1 cDNA. Femoral arterial blood pressure, measured 24 h after surgery, was lower in Coarc than in Sham rats (75 +/- 5.4 vs. 122 +/- 2.3 mmHg, P < 0.05). Aortic coarctation increased the percent of juxtaglomerular apparatuses (%JGA) containing renin and its mRNA (85 +/- 2.5 and 66 +/- 2.8 vs. 49 +/- 5.3 and 36 +/- 1.7%, Coarc vs. Sham, P < 0.05) and the intensity of hybridization signals (497 +/- 89 vs. 71 +/- 12 grains/JGA, Coarc vs. Sham, P < 0.05). In addition, recruitment of renin gene expressing cells was observed along afferent arterioles in Coarc rats, whereas renin and its mRNA were limited to the JGAs in Sham rats. Renal AT1 receptor gene expression was threefold lower in Coarc than in Sham rats. We conclude that reduction of perfusion pressure after abdominal aortic coarctation acutely enhances renin gene expression and downregulates AT1 receptor gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of MAdCAM-1 gene expression in human intestinal microvascular endothelial cells

2005 ◽  
Vol 288 (2) ◽  
pp. C272-C281 ◽  
Author(s):  
Hitoshi Ogawa ◽  
David G. Binion ◽  
Jan Heidemann ◽  
Monica Theriot ◽  
Pamela J. Fisher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Microvascular Endothelial Cells ◽  
Cellular Density ◽  
Tnf Α ◽  
Gene And Protein Expression ◽  
Microvascular Endothelial

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a homing receptor preferentially expressed on gut-associated endothelial cells that plays a central role in leukocyte traffic into the mucosal immune compartment. Although the molecular mechanisms underlying endothelial ICAM-1 or E-selectin expression have been intensively investigated, the mechanisms that regulate human MAdCAM-1 expression have not been defined. We report MAdCAM-1 gene and protein expression in primary cultures of human intestinal microvascular endothelial cells (HIMEC) that was not demonstrated in human umbilical vein endothelial cells. Similar to ICAM-1 and E-selectin expression, MAdCAM-1 gene expression in HIMEC was inducible with TNF-α, IL-1β, or LPS activation. However, in striking contrast to ICAM-1 and E-selectin expression, MAdCAM-1 mRNA and protein expression in HIMEC was heavily dependent on culture duration and/or cellular density, suggesting a prominent role for cell-cell interaction among these endothelial cells in the expression of the mucosal addressin. MAdCAM-1 expression was inhibited by both SN-50 (NF-κB inhibitor) and LY-294002 [phosphatidylinositol 3-kinase (PI3-K) inhibitor], whereas ICAM-1 and E-selectin expression was inhibited by SN-50 but not by LY-294002. The Akt phosphorylation by TNF-α or LPS was greater at higher cell density, demonstrating a pattern similar to that of MAdCAM-1 expression. NF-κB activation was not affected by cellular density in HIMEC. MAdCAM-1 expression in human gut endothelial cells is regulated by distinct signaling mechanisms involving both NF-κB and PI3-K/Akt. These data also suggest that PI3-K/Akt is involved in the gut-specific differentiation of HIMEC, which results in expression of the mucosal addressin MAdCAM-1.

scholarly journals Renin gene expression in human kidney biopsies from patients with glomerulonephritis or graft rejection.

1995 ◽  
Vol 5 (7) ◽  
pp. 1469-1475
Author(s):  
J Wagner ◽  
S Volk ◽  
C C Haufe ◽  
A Ciechanowicz ◽  
M Paul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Graft Rejection ◽  
Enzyme Inhibitor ◽  
Quantitative Polymerase Chain Reaction ◽  
Internal Standard ◽  
Human Kidney ◽  
Endogenous Gene ◽  
Tumor Nephrectomy ◽  
Renin Gene ◽  
Renin Mrna

The expression of renin mRNA was determined by a quantitative polymerase chain reaction assay in 27 human kidney samples: (1) 15 biopsies of patients with glomerulonephritis with or without angiotensin-converting enzyme inhibitor (ACEI) treatment; (2) biopsies of six renal allografts with graft rejection; and (3) six biopsy samples from unaffected parts of tumor nephrectomy specimens as controls. After isolation of RNA, 0.5 to 1 microgram of total RNA was used for reverse transcription to generate cDNA. The human renin gene was subsequently amplified by the use of two primers spanning the second and third exons. Renin expression was quantified with a renin cDNA mutant as the internal standard. It exhibited the same primer binding sites as the endogenous gene but carried a 155-basepair deletion, thus yielding a shorter amplification product. The number of glomeruli was counted by microscopic transillumination immediately after biopsy (median, 9 per biopsy; range, 2 to 23). Renin mRNA was expressed as femtograms of renin mRNA per glomerulus. Renin gene expression was lower in glomerulonephritic patients without ACEI treatment compared with that in control tumor nephrectomy samples, i.e., 63 +/- 20 (N = 7) versus 250 +/- 50 fg (N = 6) of renin mRNA/glomerulus, (P < 0.02), although plasma renin concentration in the glomerulonephritic patients was in the normal range. Significantly higher renin mRNA expression was found in glomerulonephritic patients treated with ACEI, i.e., 210 +/- 50 (N = 8) compared with 63 +/- 20 (N = 7) fg of renin mRNA/glomerulus in patient not treated with ACEI (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Transcription factor NF-κB participates in regulation of epithelial cell turnover in the colon

2000 ◽  
Vol 279 (6) ◽  
pp. G1282-G1291 ◽  
Author(s):  
Mehmet Sait Inan ◽  
Veronica Tolmacheva ◽  
Qiang-Shu Wang ◽  
Daniel W. Rosenberg ◽  
Charles Giardina
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Epithelial Cell ◽  
Dna Binding ◽  
Epithelial Cells ◽  
Knockout Mice ◽  
Nuclear Antigen ◽  
Cell Turnover ◽  
Tnf Α

The transcription factor nuclear factor (NF)-κB regulates the expression of genes that can influence cell proliferation and death. Here we analyze the contribution of NF-κB to the regulation of epithelial cell turnover in the colon. Immunohistochemical, immunoblot, and DNA binding analyses indicate that NF-κB complexes change as colonocytes mature: p65-p50 complexes predominate in proliferating epithelial cells of the colon, whereas the p50-p50 dimer is prevalent in mature epithelial cells. NF-κB1 (p50) knockout mice were used to study the role of NF-κB in regulating epithelial cell turnover. Knockout animals lacked detectable NF-κB DNA binding activity in isolated epithelial cells and had significantly longer crypts with a more extensive proliferative zone than their wild-type counterparts (as determined by proliferating cell nuclear antigen staining and in vivo bromodeoxyuridine labeling). Gene expression profiling reveals that the NF-κB1 knockout mice express the potentially growth-enhancing tumor necrosis factor (TNF)-α and nerve growth factor-α genes at elevated levels, with in situ hybridization localizing some of the TNF-α expression to epithelial cells. TNF-α is NF-κB regulated, and its upregulation in NF-κB1 knockouts may result from an alleviation of p50-p50 repression. NF-κB complexes may therefore influence cell proliferation in the colon through their ability to selectively activate and/or repress gene expression.

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