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Armin Kurtz

Publications and source records attributed to Armin Kurtz.

At least 37 records · Page 2Linked to original sources
PubMed2003

Differential regulation of renin and Cox-2 expression in the renal cortex of C57Bl/6 mice.

Based on the controversy about the relevance of cyclooxygenase-2 (Cox-2)-derived prostanoids from the macula densa for the control of the renin system, this study aimed to determine the interrelation between Cox-2 and renin expression in the mouse kidney. In control mice renin mRNA was readily detectable whilst renocortical Cox-2 mRNA abundance was at the detection limit of the RNase protection assay and no specific signals for Cox-2 were obtained by in situ hybridization or Western blot analysis. Experimental maneuvers such as low-salt diet, treatment with loop diuretics or angiotensin I converting enzyme inhibitors clearly increased renin mRNA abundance up to sevenfold, but under none of these conditions renocortical Cox-2 mRNA levels were significantly changed. Moreover, the strong stimulation of renin expression by angiotensin I-converting enzyme inhibition was not changed by the cyclooxygenase inhibitor ibuprofen, which in turn clearly lowered tissue prostanoid content. Our data suggest a marked divergence of renin and Cox-2 expression in the kidney cortex of C57Bl/6 mice with no clear evidence for a role of Cox-2-derived prostanoids from the macula densa in the regulation of renin expression.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Parallel down-regulation of chloride channel CLC-K1 and barttin mRNA in the thin ascending limb of the rat nephron by furosemide.

In the past few years the pivotal role of kidney Cl(-)channels (ClC-K) channels in maintaining salt and water homeostasis in the kidney has been established. The aim of the present study was to investigate the influence of the loop diuretic furosemide on the gene expression of the kidney chloride channel ClC-K1 and its recently described functional subunit barttin. Male Sprague Dawley rats received the loop diuretic furosemide (12 mg/kg/day) for 6 days. Rats had free access to 0.9% NaCl, 0.1%KCl solution to prevent volume depletion. Localisation and regulation of ClC-K1 and barttin mRNA was analysed by RNase protection and in situ hybridisation. Nephron-specific regulation was investigated by microdissection and real-time PCR quantification. In furosemide-treated rats ClC-K1 mRNA decreased to half in the inner medulla. In the renal cortex and outer medulla ClC-K1 mRNA levels were weak and did not change. Under furosemide treatment barttin mRNA was regulated in parallel with ClC-K1 mRNA. A significant mRNA decrease occurred after furosemide treatment in inner medulla (0.50 fold), whereas cortical and outer medulla levels remained unaffected. (35)S in situ hybridisation confirmed the regulation and distribution seen in the RNase protection assay experiments. Microdissection of the inner medullary collecting duct and thin limb of Henle's loop followed by real-time PCR revealed that CLC-K1 and barttin mRNA regulation in inner medulla was limited to the thin limb; mRNA levels in collecting ducts were not affected by furosemide treatment. Our findings imply that during furosemide treatment selective down-regulation of ClC-K1 and barttin mRNAs in thin limb plays a role in maintaining salt and water homeostasis.

Actins↗
PubMed2003

The cellular oxygen tension regulates expression of the endoplasmic oxidoreductase ERO1-Lalpha.

The formation of disulfide bonds in the endoplasmic reticulum requires protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin 1 (ERO1) that reoxidizes PDI. We report here that the expression of the rat, mouse and human homologues of ERO1-Like protein alpha but not of the isoform ERO1-Lbeta are stimulated by hypoxia in rats vivo and in rat, mouse and human cell cultures. The temporal pattern of hypoxic ERO1-Lalpha induction is very similar to that of genes triggered by the hypoxia inducible transcription factor (HIF-1) and is characteristically mimicked by cobalt and by deferoxamine, but is absent in cells with a defective aryl hydrocarbon receptor translocator (ARNT, HIF-1beta). We speculate from these findings that the expression of ERO1-Lalpha is probably regulated via the HIF-pathway and thus belongs to the family of classic oxygen regulated genes. Activation of the unfolded protein response (UPR) by tunicamycin, on the other hand, strongly induced ERO1-Lbeta and more moderately ERO1-Lalpha expression. The expression of the two ERO1-L isoforms therefore appears to be differently regulated, in the way that ERO1-Lalpha expression is mainly controlled by the cellular oxygen tension, whilst ERO1-Lbeta is triggered mainly by UPR. The physiological meaning of the oxygen regulation of ERO1-Lalpha expression likely is to maintain the transfer rate of oxidizing equivalents to PDI in situations of an altered cellular redox state induced by changes of the cellular oxygen tension.

Actins↗
PubMed2003

Oxygen tension regulates the expression of a group of procollagen hydroxylases.

In this study, we have characterized the influence of hypoxia on the expression of hydroxylases crucially involved in collagen fiber formation, such as prolyl-4-hydroxylases (Ph4) and procollagen lysyl-hydroxylases (PLOD). Using the rat vascular smooth muscle cell line A7r5, we found that an hypoxic atmosphere caused a characteristic time-dependent five- to 12-fold up-regulation of the mRNAs of the two P4h alpha-subunits [alphaI (P4ha1) and alphaII (P4ha2)] and of two lysylhydroxylases (PLOD1 and PLOD2). These effects of hypoxia were mimicked by the iron-chelator deferoxamine (100 micro m) and by cobaltous chloride (100 micro m). The hypoxic induction of these genes was also seen in the mouse juxtaglomerular As4.1 cell line and mouse hepatoma cell line Hepa1 but was almost absent in the mutant cell line Hepa1C4, which is defective for the hypoxia-inducible transcription factor 1 (HIF-1). In addition, the enzyme expression was induced by hypoxia in mouse embryonic fibroblasts but not in embryonic fibroblasts lacking the HIF-1alpha subunit. These findings indicate that hypoxia stimulates the gene expression of a cluster of hydroxylases that are indispensible for collagen fiber formation. Strong indirect evidence, moreover, suggests that the expression of these enzymes during hypoxia is coordinated by HIF-1.

Animals↗
PubMed2003

Cytokines down-regulate alpha1-adrenergic receptor expression during endotoxemia.

OBJECTIVE: The reduced pressure response to norepinephrine in septic patients has directed our interest to the regulation of alpha1-adrenergic receptors in vitro and in vivo during conditions mimicking acute sepsis. DESIGN: Prospective animal trial followed by a controlled cell culture study. SETTING: Laboratory of the Department of Anesthesiology. SUBJECTS: Male Sprague-Dawley rats weighing 200 to 250 g and a mesangial cell line. INTERVENTIONS: Experimental endotoxemia was induced in rats with lipopolysaccharide, and blood pressure dose-response studies with norepinephrine were performed. Alpha1-receptor gene expression was determined in various organs by a specific RNase protection assay, and tissue concentrations of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha were measured. Rat renal mesangial cells were incubated with these cytokines or with nitric oxide donors to investigate the regulation of alpha1-adrenergic receptors during severe inflammation on a cellular level. MEASUREMENTS AND MAIN RESULTS: The pressor effect of norepinephrine was markedly diminished during endotoxemia. The animals showed down-regulated mRNA levels of alpha1A-, alpha1B- and alpha1D-receptors in all organs investigated, and the tissue concentrations of interleukin-1beta and tumor necrosis factor-alpha were highly increased during experimental endotoxemia. Incubation of cultured rat renal mesangial cells with the cytokines resulted in diminished alpha -receptor gene expression and [3H]prazosin binding capacity, whereas incubation of the cells with nitric oxide donors did not affect alpha1B-receptor expression. In line, blocking of cytokine-induced nitric oxide synthesis by coincubation of mesangial cells with N(G)-nitro-L-arginine methyl ester did not influence cytokine-induced down-regulation of alpha1B-receptors. CONCLUSIONS: Our data show that endotoxemia causes a systemic down-regulation of alpha1-receptors on the level of gene expression and suggest that this effect is likely mediated by proinflammatory cytokines in a synergistic but nitric oxide-independent fashion. We propose that this down-regulation of alpha1-adrenergic receptors contributes to the attenuated blood pressure response to norepinephrine and, therefore, to septic circulatory failure in patients.

Animals↗
PubMed2002

Preserved macula densa-dependent renin secretion in A1 adenosine receptor knockout mice.

Recent studies demonstrated that the influence of the macula densa on glomerular filtration is abolished in adenosine A(1) receptor (A(1)AR) knockout mice. Inasmuch as the macula densa not only regulates glomerular filtration but also controls the activity of the renin system, the present study aimed to determine the role of the A(1)AR in macula densa control of renin synthesis and secretion. Although a high-salt diet over 1 wk suppressed renin mRNA expression and renal renin content to similar degrees in A(1)AR(+/+), A(1)AR(+/-), and A(1)AR(-/-) mice, stimulation of Ren-1 mRNA expression and renal renin content by salt restriction was markedly enhanced in A(1)AR(-/-) compared with wild-type mice. Pharmacological blockade of macula densa salt transport with loop diuretics stimulated renin expression in vivo (treatment with furosemide at 1.2 mg/day for 6 days) and renin secretion in isolated perfused mouse kidneys (treatment with 100 microM bumetanide) in all three genotypes to the same extent. Taken together, our data are consistent with the concept of a tonic inhibitory role of the A(1)AR in the renin system, whereas they indicate that the A(1)AR is not indispensable in macula densa control of the renin system.

Animals↗
PubMed2002

General inhibition of renocortical cyclooxygenase-2 expression by the renin-angiotensin system.

Because across-the-board data indicate that renin and cyclooxygenase-2 (COX-2) expression in the kidney cortex are regulated in parallel and because ANG II can inhibit COX-2 expression, the purpose of our study was to characterize a potential general inhibitory feedback of the renin-angiotensin system on renocortical COX-2 expression in vivo. Rats were fed a high-, normal-, or low-salt diet or were chronically infused with furosemide (60 mg. kg(-1). day(-1)) or the left renal artery was clipped, and the animals were treated in addition to or without the angiotensin-converting enzyme inhibitor ramipril (10 mg. kg(-1). day(-1)). A high-salt diet reduced expression of COX-2, whereas a low-salt diet, furosemide infusion, and renal artery stenosis stimulated COX-2 expression. Additional angiotensin-converting enzyme inhibition led to further increases in renocortical COX-2 expression by 62, 136, 300, 50, and 70% for a high-, normal-, and low-salt diet, furosemide infusion, and renal artery stenosis, respectively. Thus our data suggest a general inhibitory effect of the renin-angiotensin system on renocortical COX-2 expression.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Cyclic AMP stimulates renin gene transcription in juxtaglomerular cells.

Although the cyclic AMP signalling cascade is considered to be the main activator of renin gene expression in renal juxtaglomerular (JG) cells, the molecular pathways along which cAMP exerts this effect remain a matter of controversy. Here in this study we used the mouse JG cell line As4.1, which shares a number of functional similarities with native JG cells. We found that forskolin, an activator of adenylate cyclase, in the presents of IBMX time-dependently increased renin mRNA levels and prorenin secretion up to threefold. The stimulation of renin gene expression by forskolin/IBMX was markedly attenuated by an inhibitor of protein kinase A (H-89, 10 microM). Forskolin/IBMX had no effect on the decline of renin mRNA after general inhibition of transcription by actinomycin D (2 microM). Conversely, forskolin/IBMX increased the activity of a 2.8-kb fragment of the renin promoter threefold. The promoter region responsible for the stimulatory effect of forskolin/IBMX was narrowed down to three 4 bp of the mouse Ren1(C) gene, which are known as putative CRE-sites. The CRE-binding protein was found to be phosphorylated under forskolin/IBMX stimulation. It appears likely therefore that cAMP stimulates renin gene expression in JG cells by activating protein kinase A and subsequent phosphorylation of the CRE-binding protein.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Barttin increases surface expression and changes current properties of ClC-K channels.

The term Bartter syndrome encompasses a heterogeneous group of autosomal recessive salt-losing nephropathies that are caused by disturbed transepithelial sodium chloride reabsorption in the distal nephron. Mutations have been identified in the NKCC2 (Na(+)-K(+)-2Cl(-)) cotransporter and ROMK potassium channel, which cooperate in the process of apical sodium chloride uptake, and ClC-Kb chloride channels, which mediate basolateral chloride release. Recently, mutations in barttin, a protein not related to any known ion transporter or channel, were described in BSND, a variant of Bartter syndrome associated with sensorineural deafness. Here we show that barttin functions as an activator of ClC-K chloride channels. Expression of barttin together with ClC-K in Xenopus oocytes increased ClC-K current amplitude, changed ClC-K biophysical properties, and enhanced ClC-K abundance in the cell membrane. Co-immunoprecipitation revealed a direct interaction of barttin with ClC-K. We performed in situ hybridization on rat kidney slices and RT-PCR analysis on microdissected nephron segments to prove co-expression of barttin, ClC-K1 and ClC-K2 along the distal nephron. Functional analysis of BSND-associated point mutations revealed impaired ClC-K activation by barttin. The results demonstrate regulation of a CLC chloride channel by an accessory protein and indicate that ClC-K activation by barttin is required for adequate tubular salt reabsorption.

Animals↗
PubMed2002

Angiotensin II inhibits renin gene transcription via the protein kinase C pathway.

Angiotensin II (ANGII) inhibits renin gene expression in vivo, a mechanism considered to be a physiologically important negative feedback of the renin-angiotensin-system. How this particular effect of ANGII is achieved at the cellular level is unknown. Our study therefore aimed to determine whether ANGII exerts a direct effect on renin gene expression and, if so, to characterise the molecular mechanisms involved. In the mouse renal juxtaglomerular cell line As4.1, ANGII decreased steady-state renin mRNA levels and prorenin secretion time and concentration (EC(50) 100 nmol/l) dependently. The effects of ANGII were blunted by the protein kinase C (PKC) inhibitor bisindolylmaleimide I and mimicked by the PKC activator phorbol 12-myristate-13-acetate (PMA) (EC(50) 10 nmol/l). ANGII also inhibited renin promoter activity PKC-dependently. The inhibitory sequences triggered by ANGII appear to reside within the first 2.9 kb in the 5'-flanking region of the mouse ren1c gene but are not related to the two canonical activator protein-1 (AP-1) binding sites at positions -16 to -22 and -141 to -147. In summary, our data suggest that ANGII acts directly on renal juxtaglomerular cells to inhibit renin gene transcription through the PKC pathway. Since the PKC pathway can be activated by a variety of hormones it represents a powerful and probably rather important downstream pathway in the control of renin gene expression.

Angiotensin II↗
PubMed2002

Cyclo-oxygenase-2 inhibition increases blood pressure in rats.

1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but significant effects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the effect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible influence of salt intake on the effects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F(1alpha) in WKY rats fed a normal salt diet (0.6% NaCl, wt wt(-1)), without affecting serum thromboxane (TX)B(2) levels. 3 Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt(-1)), but not in rats on low salt intake (0.02% NaCl, wt wt(-1)). 4 Rofecoxib significantly decreased plasma levels of 6-keto PGF(1alpha) in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no influence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was significantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib, fluid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Nephron specific regulation of chloride channel CLC-K2 mRNA in the rat.

BACKGROUND: This study investigated the influence of salt intake on the nephron specific gene expression of the kidney chloride channel CLC-K2. To this end, male Sprague-Dawley rats were fed a low (0.02% wt/wt), normal (0.6% wt/wt), or high salt (8% wt/wt) diet for ten days, or they received the loop diuretic furosemide (12 mg/kg/day) for six days. METHODS: Expression and regulation of messenger RNA for CLC-K2 was demonstrated by RNase protection assay and in situ hybridization in kidney cortex, outer medulla and inner medulla. Tubular localization and regulation were determined precisely by reverse transcription-polymerase chain reaction (RT-PCR) and real time PCR of microdissected nephron segments. RESULTS: In situ hybridization analysis and RNase protection assay of the total kidney revealed a down-regulation of CLC-K2 mRNA in the high salt diet rats and an up-regulation of CLC-K2 mRNA in furosemide treated rats, which were restricted to the outer medulla. Microdissection of collagenase treated kidney revealed CLC-K2 mRNA expression in the outer medullary thick ascending limb (mTAL), cortical thick ascending limb (cTAL), distal convoluted tubule (DCT), connecting tubule and cortical collecting duct (CNT/CCD), and outer medullary collecting duct (OMCD), whereas no signals were detected in proximal convoluted and straight tubules (PCT and PST), descending thin limb from the outer medulla (dTL), descending and ascending thin limb from the inner medulla (TL), inner medullary collecting duct (IMCD) and glomeruli (glom). Using RT-PCR and real time PCR, the changing levels of CLC-K2 mRNA after furosemide treatment or high salt diet were restricted to the mTAL, whereas CLC-K2 mRNA levels in cTAL and OMCD were not changed in furosemide or high salt rats compared to time paired controls. CONCLUSIONS: Given that CLC-K2 expressed in the thick ascending limb of Henle's loop is responsible for net chloride reabsorption in this part of the nephron, our findings suggest that in states of surplus salt and in states of severe salt deprivation, selective regulation of CLC-K2 mRNA plays a role in the adaptation of the kidney to different salt loads.

Animals↗
PubMed2002

Gene expression of prostanoid forming enzymes along the rat nephron.

BACKGROUND: To obtain information about the general capability of nephron segments to elaborate prostanoids, we determined the gene expression of key enzymes for prostanoid formation. METHODS: For this goal mRNAs were assayed for cyclooxygenases-1 and -2 as well as for the synthases of prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostacyclin (PGI2) and thromboxane A2 (TXA2) in microdissected rat nephron segments by RT-PCR. RESULTS: Cyclooxygenase-1 (COX-1) mRNA was strongly expressed in all segments of the collecting ducts and to a lesser extent in glomeruli. COX-2 mRNA was found in the cortical thick ascending limb of Henle, and weaker expression also was detected in glomeruli. The lipocalin-type PGD synthase mRNA displayed a broad expression pattern in the cortex and outer medulla, including proximal convoluted tubule, thick ascending limb of Henle, distal convoluted tubule, and cortical and outer medullary collecting duct. The hematopoietic PGD synthase mRNA was restricted to the outer medullary collecting duct, and the membrane-associated PGE-synthase mRNA was exclusively expressed in the whole collecting duct system. Prostacylin-synthase mRNA was found in the whole kidney, but not in any microdissected nephron segment analyzed in this study. TXA-synthase mRNA was expressed in glomeruli. CONCLUSION: Given that the existence of cyclooxygenase in combination with the different PG-synthases is a prerequisite for the formation of prostanoids, our data suggest that PGD2 is mainly formed in the thick ascending limb and in the collecting duct, while PGE2 appears to be mainly generated by the collecting ducts. Probably no formation of PGI2 occurs within the nephron. Whether TXA2 can be formed by nephron segments remains questionable.

Animals↗
PubMed2002

Low tonicity mediates a downregulation of cyclooxygenase-1 expression by furosemide in the rat renal papilla.

It is well known that loop diuretics enhance the renal excretion of prostanoids; therefore, this study aimed to characterize the influence of loop diuretics on the intrarenal expression of cyclooxygenases, which are the key enzymes for prostanoid formation. Male Sprague-Dawley rats were infused with furosemide (12 mg/kg per d) for 6 d, and the expression of cyclooxygenase-1 and -2 (Cox-1 and Cox-2) was analyzed in the different kidney zones. Furosemide increased Cox-2 mRNA expression approximately twofold in the cortex, but it left Cox-1 mRNA expression unaltered there. In the outer medulla, furosemide changed neither Cox-1 nor Cox-2 mRNA expression. In the inner medulla, however, furosemide decreased Cox-1 and Cox-2 mRNA levels to approximately 30% and 60% of their control levels, respectively. The downregulation of mRNA was paralleled by a decrease of Cox protein in the collecting ducts and interstitial cells. Moreover, tissue prostaglandin E(2) (PGE(2)) concentrations in the papilla were markedly decreased by furosemide to about 30% of the control level. Furosemide lowered urine osmolality from 1550 mosmol/kg to 480 mosmol/kg; therefore, further consideration was given to the influence of tonicity as a possible mediator of the effects of furosemide on the Cox expression. Water loading was therefore used to reduce the medullary tonicity by a second maneuver. Water loading led to a similar reduction in papillary Cox mRNA expression and PGE(2) content like furosemide. To investigate the influence of the osmolarity on the expression of Cox and the production of PGE(2) under defined in vitro conditions, inner medullary collecting duct cells were incubated with culture medium containing graded amounts of NaCl ranging from 200 mmol/L to 600 mmol/L, and Cox-1 and Cox-2 mRNA abundance were determined after 24 h an 48 h. Cox-1 and Cox-2 mRNA abundance changed in parallel with the osmolarity. The data suggest that loop diuretics decrease the expression of cyclooxygenases and consequently tissue PGE(2) concentrations in the kidney inner medulla. This effect could be related to the breakdown of the papillary osmotic gradient induced by loop diuretics.

Actins↗
PubMed2002

Cyclosporine A suppresses cyclooxygenase-2 expression in the rat kidney.

On the basis of recent evidence that the cyclooxygenase-2 (COX-2) gene promoter contains functional binding sites for the nuclear factor of activated T cells (NFAT) and that COX-2 is expressed in a regulated fashion in the kidney, this study aimed to assess the effect of immunosuppressants on COX-2 expression in the kidney. Therefore, Wistar-Kyoto rats were treated with cyclosporine A (CsA; 15 mg/kg per day) or tacrolimus (5 mg/kg per day) for 7 d each. Both drugs markedly lowered COX-2 expression while COX-1 expression remained unaltered. Furthermore, CsA blunted the increase of renocortical COX-2 expression in response to low salt intake or a combination of low-salt diet with the ACE inhibitor ramipril (10 mg/kg per day), which strongly stimulates renocortical COX-2 expression. At the same time, calcineurin inhibitors moderately enhanced basal as well as stimulated renin secretion and renin gene expression. These findings suggest that inhibition of calcineurin could be a crucial determinant for the regulated expression of COX-2 in the kidney. Inhibition of COX-2 expression may therefore at least in part account for the well-known adverse effects of immunosuppressants in the kidney. Moreover, our data suggest that the stimulation of the renin system by low salt and by ACE inhibitors is not essentially mediated by COX-2 activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Tumor necrosis factor-alpha inhibits renin gene expression.

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-alpha, 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-alpha may exert its effects on the cardiovascular system through modulation of renal renin synthesis. Therefore we have tested the effect of TNF-alpha 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-alpha (TNF-alpha knockout mice). TNF-alpha 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-alpha also attenuated forskolin-stimulated renin gene expression in primary cultures of mouse JG cells. Mice lacking the TNF-alpha 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-alpha knockout mice. Our data suggest that TNF-alpha inhibits renin gene transcription at the cellular level and thus may act as a modulator of renin synthesis in (physio)pathological situations.

Animals↗
PubMed2002

Angiotensin II feedback is a regulator of renocortical renin, COX-2, and nNOS expression.

Salt restriction leads to parallel increases of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys. Because the upregulation of these genes is strongly enhanced if salt restriction is combined with inhibition of the renin-angiotensin-aldosterone system, our study aimed to find out whether the juxtaglomerular expressions of renin, COX-2, and nNOS are subject to a common direct negative feedback control by ANG II. For this purpose, male Sprague-Dawley rats were fed a low-salt diet (0.02% wt/wt) with or without additional treatment with the ANG I-converting enzyme (ACE) inhibitor ramipril (10 mg x kg body wt(-1) x day(-1)) for 1 wk, and renocortical renin, COX-2, and nNOS mRNAs were assayed. To narrow down possible indirect effects of the ACE inhibitor that may result from insufficient aldosterone production, the animals received mineralocorticoid substitution with fludrocortisone (6 mg. kg body wt(-1) x day(-1)). Thus mineralocorticoid substitution prevented the fall of systolic blood pressure and of glomerular filtration induced by ramipril in rats on low-salt diet. Although fludrocortisone had no effect on basal renin, COX-2, and nNOS mRNA, it clearly attenuated the threefold increases of both renin and COX-2 mRNA in response to low-salt diet. In rats on low-salt diet, ramipril further increased renin mRNA ninefold, COX-2 mRNA fourfold, and nNOS 2.5-fold in the absence of fludrocortisone. In the presence of fludrocortisone, ramipril increased renin mRNA 10-fold, COX-2 mRNA 2.5-fold, and nNOS mRNA 2.5-fold. These data indicate that mineralocorticoid substitution lowers the overall expression of juxtaglomerular renin and COX-2 during low-salt intake and attenuates a further rise of COX-2 expression by ACE inhibition, but it does not change the stimulatory effect of ACE inhibition on renin and nNOS expression. We conclude that the expression of renin, COX-2, and nNOS in the juxtaglomerular apparatus during low-salt diet is markedly limited by a direct feedback inhibition through ANG II.

Angiotensin-Converting Enzyme Inhibitors↗