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Biomedical subjects

Kamal Rahmouni

Publications and source records attributed to Kamal Rahmouni.

At least 19 recordsLinked to original sources
PubMed2007

The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells.

A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from -1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, beta-estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at -20 and -217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of beta-estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the -20 and -217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues.

Adipose Tissue↗
PubMed2006

Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin.

Leptin is an adipocyte-derived hormone that plays an important role in the regulation of energy homeostasis through its action in the central nervous system. Leptin decreases body weight by promoting satiety and increasing thermogenesis via increasing sympathetic nerve activity (SNA) to brown adipose tissue. Leptin also increases renal SNA and arterial pressure. The arcuate nucleus is considered as a major nucleus for leptin action on energy homeostasis. We tested whether leptin action in the arcuate nucleus simultaneously activates SNA to brown adipose tissue and the kidney. The sympathetic and cardiovascular responses to intra-arcuate injection of leptin were compared with those evoked by intracerebroventricular administration of leptin in rat. Intracerebroventricular administration of leptin (10 mug) caused a significant increase in SNA to brown adipose tissue and the kidney. Intracerebroventricular leptin also increased mean arterial pressure. Direct injection of leptin (500 ng) into the arcuate nucleus increased both brown adipose tissue (254+/-49%; P<0.001 versus vehicle) and renal SNA (111+/-31%; P<0.001 versus vehicle). Microinjection of leptin into the arcuate nucleus also produced a substantial increase in mean arterial pressure (from 82+/-3 to 100+/-7 mm Hg; P=0.02). These data demonstrate that leptin action in the arcuate nucleus of the hypothalamus is important for the control of sympathetic outflow to both brown adipose tissue and the kidney. These results also suggest that the cardiovascular effects of leptin might be evoked by the action of this hormone in the arcuate nucleus of the hypothalamus.

Adipose Tissue, Brown↗
PubMed2006

Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome.

AIM: To review the potential role of leptin, hyperleptinaemia and leptin resistance in the cardiovascular and endocrine complications of metabolic syndrome. METHODS: Review of literature listed in Medline. RESULTS: Hyperleptinaemia is common in obesity and reflects increased adiposity and leptin resistance. Nevertheless, leptin resistance may not be complete as several actions of leptin, such as cardiovascular sympatho-activation, might be preserved in obese subjects known to be resistant to the metabolic effects of leptin (i.e. selective leptin resistance). Notably, the renal and sympathetic actions of leptin may play an important role in the pathogenesis of hypertension related to obesity and metabolic syndrome. Furthermore, the lipotoxic effect of leptin resistance may cause insulin resistance and beta cell dysfunction, increasing the risk of type 2 diabetes. Leptin has also been shown to possess proliferative, pro-inflammatory, pro-thrombotic, and pro-oxidative actions. CONCLUSION: Hyperleptinaemia and leptin resistance may contribute to hypertension, impaired glucose metabolism, and pro-atherogenic state in obesity and metabolic syndrome.

Animals↗
PubMed2005

Lack of dilator effect of leptin in the hindlimb vascular bed of conscious rats.

Leptin acts in the hypothalamus to decrease appetite and increase sympathetic nerve activity. Some in vitro studies have suggested that leptin may possess vasodilator actions that oppose sympathetically mediated vasoconstriction. We tested whether leptin is a vasodilator of the hindlimb vascular bed in vivo, and also whether it alters vasodilation to acetylcholine or sodium nitroprusside. In conscious instrumented Sprague-Dawley rats we measured iliac blood flow responses to local arterial infusion of acetylcholine (0.1 and 1 microg/min) and sodium nitroprusside (1 and 10 microg/min) before and after 2 h of intra-arterial leptin (at doses of 0.1 or 1 mg/kg, n=10 each) or vehicle (n=10). Leptin infusion over 2 h did not change mean arterial pressure, heart rate or iliac flow and conductance. In addition, leptin did not significantly alter the vasodilation (increase in the conductance ratio between infused and non-infused arteries) induced by acetylcholine, whereas pre-treatment with a nitric oxide synthesis inhibitor, N(G)-nitro-L-arginine methyl ester, significantly attenuated the vasodilation to acetylcholine. Leptin also did not affect the vasodilation to sodium nitroprusside. Lack of effect of leptin on vasodilator function could not be due to the activation of the sympathetic nervous system because lumbar sympathoactivation was obtained only 4 h after the iliac infusion of 1 mg/kg/h of leptin. These findings are in accordance with our previous results and argue against a meaningful direct dilator action of leptin on resistance vessels in vivo.

Acetylcholine↗
PubMed2005

Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome.

McKusick-Kaufman syndrome (MKS) is an autosomal recessive disorder characterized by post-axial polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. Mutations in the MKKS gene have also been shown to cause some cases of Bardet-Biedl syndrome (BBS) which is characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities and hypogenitalism with secondary features of hypertension and diabetes. Although there is overlap in clinical features between MKS and BBS, MKS patients are not obese and do not develop retinopathy or have learning disabilities. To further explore the pathophysiology of BBS and the related disorder MKS, we have developed an Mkks(-/-) mouse model. This model shows that the absence of Mkks leads to retinal degeneration through apoptosis, failure of spermatozoa flagella formation, elevated blood pressure and obesity. The obesity is associated with hyperphagia and decreased activity. In addition, neurological screening reveals deficits in olfaction and social dominance. The mice do not have polydactyly or vaginal abnormalities. The phenotype of the Mkks(-/-) mice closely resembles the phenotype of other mouse models of BBS (Bbs2(-/-) and Bbs4(-/-)). These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations.

Abnormalities, Multiple↗
PubMed2005

Endothelial effects of leptin: implications in health and diseases.

Leptin is an adipocyte-derived hormone that plays a major role in the regulation of energy homeostasis through its action in the central nervous system. Leptin also acts on several peripheral tissues, including the vascular endothelium. The leptin receptor has been identified in endothelial cells. Leptin action on the endothelium modulates several physiologic processes, with potential implications in pathophysiologic diseases associated with obesity. Leptin stimulation of angiogenesis has attracted attention because of its potential involvement in retinopathy and atherosclerosis. Leptin activation of endothelial oxidative stress also has implications in atherosclerosis and inflammation. However, data on the impact of the endothelial effect of leptin on arterial pressure are contrasting. Although some investigators have shown that leptin action on the endothelial nitric oxide system tends to decrease arterial pressure, others have shown no contribution from the endothelial effect of leptin to the control of arterial pressure. Further characterization of the endothelial effects of leptin will, it is hoped, help in the understanding of the different pathophysiologic diseases associated with obesity.

Animals↗
PubMed2005

Role of selective leptin resistance in diet-induced obesity hypertension.

Leptin is an adipocyte-derived hormone that plays a key role in the regulation of body weight through its actions on appetite and metabolism. Leptin also increases sympathetic nerve activity (SNA) and blood pressure. We tested the hypothesis that diet-induced obesity is associated with resistance to the metabolic actions of leptin but preservation of its renal SNA and arterial pressure effects, leading to hypertension. Mice were fed a high-fat diet for 10 weeks to induce moderate obesity. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular leptin was significantly attenuated in the obese mice. Regional SNA responses to leptin were differentially altered in diet-induced obese mice. Renal SNA response to leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated in obese mice. Radiotelemetric arterial pressure was approximately 10 mmHg higher in obese mice. Furthermore, the increase in arterial pressure in response to long-term (12 days) leptin treatment was preserved in obese mice. Thus, mice with diet-induced obesity exhibit circulating hyperleptinemia and resistance to the metabolic actions of leptin. However, there is preservation of the renal sympathetic and arterial pressure responses to leptin, which represent a potential mechanism for the adverse cardiovascular consequences of obesity.

Adipose Tissue, Brown↗
PubMed2004

Obesity-associated hypertension: new insights into mechanisms.

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.

Adiponectin↗
PubMed2004

Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity.

Adipose tissue represents an important source of angiotensinogen (AGT). We investigated the effect of obesity induced by a high-fat diet on the expression of mouse (mAGT) and human AGT (hAGT) genes in liver, kidney, and heart and different adipose depots in normal mice (C57BL/6J), and in transgenic mice expressing the hAGT gene under the control of its own promoter. Mice were fed a high-fat diet (45% kcal) or normal chow (10% kcal) for 10 and 20 wk. The expression of mAGT and hAGT mRNA was quantified using an RNAse protection assay. Mice on the high-fat diet exhibited increased weight, fat mass, and plasma leptin. Expression of mAGT or hAGT genes was not affected by high-fat diet in nonadipose tissues, brown adipose tissue, or subcutaneous white fat. In contrast, high-fat diet increased both mAGT and hAGT gene expression in visceral adipose depots (omental, reproductive, and perirenal fat). Thus obesity-induced by a high-fat diet is associated with a tissue-specific increased expression of both mouse and human AGT genes in intra-abdominal adipose tissue. Our findings also suggest that 1.2 kb of regulatory sequences present in the hAGT transgene are sufficient to transcriptionally respond to a high-fat diet in an adipose-specific and depot-specific manner.

Adipose Tissue↗
PubMed2004

Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin.

The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.

Adipose Tissue, Brown↗
PubMed2004

Leptin and the cardiovascular system.

Obesity is associated with increased cardiovascular morbidity and mortality, in part through development of hypertension. Recent observations suggest that the cardiovascular actions of leptin may help explain the link between excess fat mass and cardiovascular diseases. Leptin is an adipocyte-derived hormone that acts in the central nervous system to promote weight loss by decreasing food intake and increasing metabolic rate. Leptin causes a significant increase in overall sympathetic nervous activity, which appears to be due to direct hypothalamic effects and is mediated by neuropeptide systems such as the melanocortin system and corticotropin-releasing hormone. Renal sympathoactivation to leptin is preserved in the presence of obesity, despite resistance to the metabolic effects of leptin. Such selective leptin resistance, in the context of circulating hyperleptinemia, could predispose to obesity-related hypertension. Some in vitro studies have suggested that leptin may have peripheral actions such as endothelium-mediated vasodilation that might oppose sympathetically induced vasoconstriction. However, we and others have shown that leptin does not have direct vasodilator effects in vivo. The fact that chronic leptin administration or overexpression of leptin produces hypertension supports the concept that the hemodynamic actions of leptin are due predominantly to sympathetic activation. Exploration of the sites and mechanisms of leptin resistance should provide novel therapeutic strategies for obesity, insulin resistance, and hypertension.

Animals↗
PubMed2003

Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin.

Central melanocortin signaling plays an important role in regulation of energy homeostasis by leptin and insulin. We investigated the interaction between leptin, insulin, and melanocortin-4 receptors (MC-4Rs) in the control of renal sympathetic nerve activity (RSNA) in mice. We compared the effects of intracerebroventricular (ICV) administration of leptin, insulin, MC-3/4R agonist (MTII), and corticotrophin-releasing factor (CRF) on RSNA in leptin receptor-deficient (db/db) mice, MC-4R knock-out mice, and their wild-type controls. ICV administration of leptin and MTII caused a significant and dose-dependent increase in RSNA in control mice. As expected, leptin had no significant effect on RSNA in the db/db mice. Interestingly, db/db mice exhibited markedly attenuated RSNA responses to ICV administration of MTII. However, the increase in RSNA induced by insulin and CRF was comparable between db/db and control mice. In the heterozygous and homozygous MC-4R knock-out mice, the RSNA response to MTII was attenuated and abolished, respectively. The RSNA response to ICV leptin and insulin was also attenuated and abolished in the heterozygous and homozygous MC-4R knock-out mice, respectively. In contrast, CRF induced a similar increase in RSNA in the MC-4R knock-out and wild-type mice. Our data demonstrate that in the absence of leptin receptors, the sympathoexcitatory effects of melanocortin system stimulation are attenuated. In addition, the renal sympathoexcitatory responses to leptin and insulin are dependent on the MC-4R, demonstrating an important role for the MC-4R in the regulation of renal sympathetic nerve outflow by leptin and insulin.

Action Potentials↗
PubMed2002

Intracellular mechanisms involved in leptin regulation of sympathetic outflow.

Leptin acts in the hypothalamus to decrease appetite and increase sympathetic nerve activity. The leptin receptor is known to signal through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway to modulate transcription of target genes. Alteration of the activity of phosphoinositol-3 kinase (PI3K) by leptin has also been reported, and inhibition of PI3K is known to block the leptin-induced suppression of feeding. We tested the hypothesis that leptin-induced renal sympathetic nerve activation is mediated by PI3K. We evaluated renal sympathetic nerve activity (RSNA) and feeding responses of C57BL/6J mice to intracerebroventricular (ICV) administration of leptin in the presence or absence of selective inhibitors of PI3K (LY294002 or wortmannin). As expected, ICV administration of leptin decreased food intake at 4 hours and 24 hours and increased RSNA. Pretreatment with the PI3K inhibitor LY294002 markedly attenuated both the decrease in food intake and the increase in RSNA induced by leptin. Wortmannin also inhibited the RSNA response to leptin. In contrast, PI3K inhibitors did not affect the RSNA response to MTII (melanocortin-3/4 receptor agonist). Our data demonstrate that PI3K appears to play an important role in the transduction of leptin-induced changes in renal sympathetic outflow.

Androstadienes↗
PubMed2002

Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA-salt hypertension.

In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.

Angiotensinogen↗
PubMed2002

Cardiovascular and sympathetic effects of leptin.

Several studies have shown the association between obesity and hypertension. The pathophysiologic mechanisms of obesity-related hypertension remain unknown. Clinical and experimental studies have shown that obesity is associated with enhanced sympathetic nervous activity. Thus, sympathetic nerve activation seems to play a major role in obesity-associated hypertension. However, the factors responsible for this sympathoactivation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and food intake and by increasing energy expenditure through sympathetic stimulation to brown adipose tissue. Leptin also produces sympathoactivation to kidneys, hindlimb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, obesity is associated with leptin resistance, since high circulating levels of leptin were observed in obese subjects. Recent evidences indicate that this leptin resistance could be selective with preservation of sympathetic effects despite the loss of metabolic action of leptin. This suggests divergent central pathways underlying metabolic and sympathetic effects of leptin. Several neuropeptides have emerged as potent candidate mediators of leptin action in the central nervous system, including the melanocortin system, neuropeptide Y, and cortico-trophin releasing factor. A detailed understanding of the multitude and complexity of integrated neuronal circuits and neuropeptide-containing pathways in leptin action will help in understanding the pathogenesis of obesity and related disorders.

Animals↗
PubMed2002

Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications.

Leptin, an adipocyte secreted hormone, acts in the hypothalamus to inhibit appetite and promote thermogenic metabolism, thereby reducing adiposity and body weight. Leptin has multiple autonomic and cardiovascular actions, including sympathetic activation, increases in endothelium derived nitric oxide (NO), and angiogenesis. The predominant cardiovascular effect of chronic hyperleptinemia is a pressor effect mediated by increased sympathetic activity. The sympathetic and cardiovascular actions of leptin are discussed and evidence derived from studies of obese mice for the novel concept of selective leptin resistance is reviewed. This concept holds that in some obese states, there is preservation of the sympathoexcitatory actions of leptin despite resistance to the satiety and weight-reducing actions of the hormone. Selective leptin resistance might explain how hyperleptinemia could contribute to increases in sympathetic activity and arterial pressure in obese states where there is resistance to the metabolic (satiety and weight-reducing) actions of leptin. It is speculated here, that this concept may have potential implications for human obesity, which is often associated with elevated plasma leptin and partial resistance to the satiety effects of leptin. If selective leptin resistance occurs in obese humans, then leptin could contribute to the sympathetic overactivity and hypertension despite resistance to its metabolic actions.

Animals↗
PubMed2002

Influence of sodium intake on the cardiovascular and renal effects of brain mineralocorticoid receptor blockade in normotensive rats.

OBJECTIVE: We have previously shown that brain mineralocorticoid receptors (MR) participate in the control of arterial pressure and renal excretory function in normotensive rats. In the present study, we evaluate the influence of sodium intake on the control of cardiovascular and renal function by brain MR in normotensive conscious rats. We hypothesize that modulation of sodium intake affects the cardiovascular and renal effects of brain MR blockade. DESIGN AND METHODS: We examined the effect of intracerebroventricular (ICV) administration of MR antagonist (RU28318) on systolic blood pressure (SBP), heart rate, and urinary excretion of water and electrolytes in normotensive Wistar rats subjected to different dietary sodium content. Rats were fed high (8%), normal (0.4%), or depleted (0%) sodium for 3 weeks. SBP and heart rate measurements were performed using an indirect tail cuff method. Metabolic cages were used to assess renal function. RESULTS: ICV injection of 100 ng RU28318 induced a long-lasting decrease ( 0.01) in SBP in rats submitted to different sodium intake. At 8 h, the decrease in SBP did not differ between rats on high (30 +/- 5 mmHg), normal (28 +/- 6 mmHg), and low (21 +/- 3 mmHg) sodium diets. At 24 h, the decrease in SBP was also comparable between rats on different sodium diets. Increased diuresis was observed during the period 0-8 h after ICV injection of RU28318; this was less pronounced in rats on the low sodium diet. Urinary excretions of potassium and chloride were also increased during this period, particularly in rats on the high and normal sodium diets compared with rats with low sodium intake. Urinary excretion of sodium was increased only in the rats fed high and normal sodium diets. Measurement of plasma renin activity, which was suppressed and stimulated, respectively, by high and low sodium intake, indicated that the effects on SBP and renal function induced by ICV RU28318 were independent from the level of activation of the renin-angiotensin system. CONCLUSION: In contrast to our hypothesis, in normotensive Wistar rats, sodium intake does not affect the hypotension induced by brain MR blockade. However, sodium depletion attenuated the renal effects of brain MR blockade.

Animals↗