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Daniele Cusi

Publications and source records attributed to Daniele Cusi.

At least 19 recordsLinked to original sources
PubMed2007

Mechanisms of disease: The role of aldosterone in kidney damage and clinical benefits of its blockade.

In the past 10 years, many widely accepted concepts relating to aldosterone production and its pathogenetic role have changed. We now know that aldosterone is produced not only by the zona glomerulosa of the adrenal cortex, but also in the heart, blood vessels, kidney and brain; such extra-epithelial production occurs mainly during tissue repair. Also, increased aldosterone levels contribute to vessel inflammation, oxidative stress, endothelial dysfunction and organ damage. As such, aldosterone has a key role in the development of myocardial fibrosis. Anti-aldosterone treatment has proven effective in patients with heart failure. Experimental evidence regarding the role of aldosterone in kidney damage has accumulated. Aldosterone infusion can counteract the beneficial effects of treatment with angiotensin-converting-enzyme inhibitors, causing more-severe proteinuria and an increased number of vascular and glomerular lesions; treatment with aldosterone antagonists can reverse these alterations. Preliminary observations in pilot studies in humans confirm the experimental findings, supporting the hypothesis that aldosterone antagonists are renoprotective in clinical practice. Studies in larger populations with longer follow-up are needed to confirm this theory.

Aldosterone↗
PubMed2006

Arachidonic acid influences intracellular calcium handling in human osteoblasts.

The effect of arachidonic acid (AA) on intracellular Ca(2+) concentration ([Ca(2+)]i) in human osteoblasts MG63 was studied. AA caused a concentration-dependent increase in [Ca(2+)]i, mainly due to inward Ca(2+) transport from extracellular environment. Moreover, AA in Ca(2+) -free medium produced a small, transient increase of [Ca(2+)]i, indicating that AA may also trigger Ca(2+) release from intracellular stores. Because the [Ca(2+)]i response to AA was inhibited by the cyclooxygenase (COX) inhibitor indomethacin, we tested the effect of prostaglandins (PGs), products of COX pathway. PGs E1 and E2 caused an increase in [Ca(2+)]i, which, however, was far lower than that obtained with AA. The [Ca(2+)]i response to AA was not inhibited by nifedipine, suggesting that AA did not activate a voltage-dependent Ca(2+) channel. Our results indicate that AA could modulate [Ca(2+)]i in MG63 human osteoblasts, where it may influence Ca(2+) transport across both plasma and endoplasmic membranes. Furthermore, they suggest that osteoblast activity may be modulated by AA.

Alprostadil↗
PubMed2006

The 460Trp allele of alpha-adducin increases carotid intima-media thickness in young adult males.

BACKGROUND: The 460Trp allele of the alpha-adducin gene (ADD1), which is involved in a form of salt-sensitive hypertension, has been associated with patterns of target organ damage. OBJECTIVES: As carotid artery intima-media thickness (IMT) largely depends upon unknown genetic factors, besides being associated to conventional risk factors, we tested the association of the 460Trp allele of ADD1 with IMT in a well-characterized sample of young healthy normotensive subjects, to assess the role of ADD1 polymorphism without overlapping effects of age or already elevated blood pressure. METHODS: Anthropometric measurements, blood pressure (BP), and carotid artery wall IMT (high-resolution sonography and digitalized morphometry) were obtained in 420 healthy normotensive Caucasian university students. Genotypes for ADD1 were detected by automated genomic polymerase chain reaction (PCR). RESULTS: ADD1 genotypes were evenly distributed between genders. IMT was significantly larger in carriers of the 460Trp allele of ADD1, while a significant gender x ADD1 interaction (P = 0.02) demonstrated that IMT was increased only in males carrying the 460Trp allele (P < 0.001). No significant association was found in females. CONCLUSIONS: The 460Trp allele of ADD1 contributes substantially to increase carotid IMT, in a male hormonal milieu only, at least in the young age range.

Adult↗
PubMed2006

Alpha-adducin and angiotensin-converting enzyme polymorphisms in hypertension: evidence for a joint influence on albuminuria.

BACKGROUND: A single-nucleotide polymorphism (Gly460Trp) within the alpha-adducin gene (ADD1) may influence several renal phenotypes, including salt sensitivity, susceptibility to renal failure, the renal haemodynamics and confer a worse cardiovascular risks profile. However, its relationship with microalbuminuria, a marker of early renal and cardiovascular damage and an independent predictor of morbid events in hypertension, is unknown. For this reason, we related the ADD1 genetic polymorphism to urine albumin levels and other clinical variables in essential hypertensive men. The angiotensin-converting enzyme (ACE) insertion/deletion (ID) polymorphism was also evaluated because of its interactive potential with the ADD1 genotype. METHODS: Albuminuria (three overnight collections), echocardiographic left ventricular mass index, blood pressure, body mass index, renal function, glucose and lipids were measured in 238 genetically unrelated, never treated, uncomplicated Caucasian essential hypertensive men. Polymerase chain reaction or a 5' nuclease assay were used to characterize the ACE ID and ADD1 Gly460Trp variants, respectively. RESULTS: Microalbuminuria (albuminuria >or= 15 microg/min) was more frequent in patients with the ACE DD variant, but only in those with a ADD1 Gly460Gly background. In contrast, urine albumin did not differ by ACE ID genotype in the presence of mutated ADD1 Trp alleles. ADD1 polymorphisms per se were not associated with albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed among different genetic backgrounds. CONCLUSIONS: ACE DD and ADD1 Gly460Gly polymorphisms may jointly influence albuminuria in hypertensive men, 460Gly homozygosis facilitating or, possibly, the 460Trp allele mitigating the noxious renal impact of the ACE DD genotype. The data highlight further the complex pathophysiological implications of microalbuminuria in hypertension.

Adult↗
PubMed2005

RFX-1, a putative alpha Adducin interacting protein in a human kidney library.

Adducin regulates tubular absorption of sodium by modulating the expression levels of the sodium-potassium-ATPase in renal tubular cells. Adducin is a candidate gene in the pathogenesis of hypertension. Yeast two hybrid screen showed a specific interaction between human alpha Adducin and the regulatory factor for X box (RFX-1), a nuclear protein that down regulates the expression of several proteins in non neuronal cells. The interaction was confirmed in cells through co-immunoprecipitation and colocalization experiments. The binding of alpha Adducin to RFX-I and their nuclear co-localization suggests that Adducin can have a role in modulating the transcriptional regulating activity of RFX-I.

Animals↗
PubMed2005

Role of the adducin family genes in human essential hypertension.

OBJECTIVE: In both humans and rats, polymorphisms of the alpha adducin (ADD1) gene are involved in renal sodium handling, essential hypertension and some of its organ complications. Adducin functions within cells as a heterodimer composed of various combinations of three subunits that are coded by three genes (ADD1, 2, 3) each located on a different chromosome. DESIGN: These characteristics provide the biochemical basis for investigating epistatic interactions among these loci. METHODS: We examined the three adducin gene polymorphisms and their association with ambulatory blood pressure (ABPM) and with plasma levels of renin activity (PRA), endogenous ouabain (EO), in 512 newly discovered and never-treated hypertensive patients. RESULTS: Relative to carriers of the wild type (Gly/Gly) ADD1 gene, patients carrying the mutated Trp ADD1 allele had higher blood pressure (systolic blood pressure (SBP) 143.2 +/- 1.0 versus 140.6 +/- 0.6 mmHg P = 0.027 and diastolic blood pressure (DBP) 94.2 +/- 0.77 versus 92.3 +/- 0.5 mmHg, P = 0.03), lower PRA and EO, consistent with the hypothesis of the renal sodium retaining effect of the Trp allele. Polymorphisms in the ADD2 and ADD3 genes taken alone were not associated with these variables. However, the differences in SBP and DBP between the two ADD1 genotypes were greatest in carriers of the ADD3 G allele (around + 8 mmHg). The significance of the interaction between ADD1 and ADD3 ranged between P = 0.020 to P = 0.006 according to the genetic model applied. CONCLUSIONS: The interaction of ADD1 and ADD3 gene variants in humans is statistically associated with variation in blood pressure, suggesting the presence of epistatic effects among these loci.

Adult↗
PubMed2005

Urinary calcium is a determinant of bone mineral density in elderly men participating in the InCHIANTI study.

BACKGROUND: It is generally acknowledged that calcium excretion is a determinant of bone mineral density. Since data confirming this hypothesis are not conclusive, the present study evaluates the relationship between calcium excretion and volumetric bone mineral density (vBMD) in a sample of general population mostly composed of elderly subjects. METHODS: This relationship was studied in 595 subjects in good health (M/F 302/293), selected from the InCHIANTI population, an epidemiologic survey on aging in Tuscany (Italy). Of these subjects, 432 (72.6%) were 65 years old or older. Trabecular and cortical apparent vBMDs were measured by peripheral quantitative computed tomography at right tibia and standardized to age and body mass index (BMI) in each gender (z-score). RESULTS: Men in the highest tertile of calcium excretion had significantly lower trabecular vBMD, and were more likely to have a trabecular z-score of -1 or less. These results were confirmed in men older than 64 years, but not in women and younger men. Sodium excretion and 25-hydroxycolecalciferol (25(OH)D) were greater in men and women in the highest tertile. No differences among tertiles were observed for cortical vBMD, circulating levels of interleukin-1beta and interleukin-6, and intake of principal nutrients and calcium. The lower levels of vBMD z-score were confirmed in men in the highest tertile of calcium excretion, standardized to creatinine clearance, sodium excretion, plasma calcium, and logarithm of circulating 25(OH)D, and resulted to be associated with calcium excretion at multiple regression analysis in men. CONCLUSION: High calcium excretion is associated with a decreased trabecular BMD in elderly men and may predispose men to trabecular bone loss.

Adult↗
PubMed2004

Vitamin D receptor mRNA measured in leukocytes with the TaqMan fluorogenic detection system: effect of calcitriol administration.

BACKGROUND: The aim of the present study was to investigate the interactions between the circulating concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the mRNA concentration of its specific nuclear receptor in human leukocytes. METHODS: We measured vitamin D receptor (VDR) mRNA extracted from leukocytes by use of TaqMan fluorescence analysis applied to the reverse transcription-PCR (RT-PCR) technique in 16 volunteers before and after calcitriol administration. VDR mRNA was also measured in leukocytes from calcium-stone-formers (37 hypercalciuric and 34 normocalciuric patients). The relationship between VDR mRNA concentrations and genetic VDR polymorphisms was analyzed in these patients. RESULTS: Imprecision (CV) of RT-PCR was 1.3% within assay (n = 10) and 1.7% between assays (n = 4). Oral 1,25(OH)2D3 increased mean (SE) serum 1,25(OH)2D3 1.6 (0.3)-fold and VDR mRNA 1.6 (0.1)-fold 8 h after administration. The maximum VDR mRNA was reached 3.6 (1.3) h after 1,25(OH)2D3 ingestion. No differences in leukocyte VDR mRNA concentrations were found between normocalciuric and hypercalciuric stone-formers in the absence of stimulation. Finally, no association was found between VDR mRNA concentrations and genetic VDR polymorphisms in stone-formers. CONCLUSIONS: The TaqMan RT-PCR assay is a rapid and accurate method to measure VDR mRNA, and leukocytes are a useful model to study VDR and 1,25(OH)2D3 interactions. In humans, VDR mRNA is increased by agonist 1,25(OH)2D3, a finding resembling previously reported results obtained in cellular and animal models.

Adult↗
PubMed2004

Association between aldosterone synthase (CYP11B2) polymorphism and left ventricular mass in human essential hypertension.

OBJECTIVES: The aim of our study was to evaluate the relationship between aldosterone synthase gene polymorphism and cardiac dimensions in essential hypertension. BACKGROUND: Higher aldosterone synthase messenger ribonucleic acid levels in the human heart are accompanied by increased intracardiac aldosterone production, a phenomenon that is associated with cardiac fibrosis and hypertrophy. Recent evidence suggests that a polymorphism (-344C/T) in the promoter region of the aldosterone synthase gene is associated with increased constitutive aldosterone production. METHOD: Relationships between M-mode echocardiographic cardiac dimensions and aldosterone synthase -344C/T polymorphism were studied in 210 never-treated, middle-aged patients (age 41.6 +/- 1.4 years) affected by mild to moderate essential hypertension. Among these patients, 48 had the genotype -C344C, 97 had -C344T, and 65 had -T344T. Patients in the three groups were similar in terms of age, gender, body mass index, and blood pressure. RESULTS: Left ventricular (LV) mass and thickness were positively correlated with the number of T alleles: LV mass (CC, CT, and TT, respectively: 168 +/- 6.9, 179 +/- 5.2, and 193 +/- 6.9 g; p = 0.03), LV septal thickness (0.99 +/- 0.02, 1.03 +/- 0.02, and 11.08 +/- 0.03 cm, p = 0.04), PWT (0.93 +/- 0.03, 0.95 +/- 0.01, and 1.03 +/- 0.02 cm; p = 0.002), and relative wall thickness (38.3 +/- 1.2%, 38.8 +/- 0.8%, and 42.8 +/- 1.1%; p = 0.004). This trend was confirmed by linear regression, suggesting a "major gene" behavior for the T allele. Multiple regression analysis showed that this effect was independent of anthropometric and clinical factors, including adrenal aldosterone. CONCLUSIONS: Our data suggest that -344C/T polymorphism affects LV mass and thickness in essential hypertension, independent of adrenal aldosterone. A role for intracardiac aldosterone synthesis is hypothesized.

Adult↗
PubMed2003

ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy.

Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and alpha-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (alpha-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and alpha-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of alpha-adducin had the largest MBP decrease with treatment (12.7+/-1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460Gly+DD, with the least MBP decrease (3.4+/-1.7 mm Hg). Alpha-adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.

Antihypertensive Agents↗
PubMed2003

Intestinal calcium absorption is associated with bone mass in stone-forming women with idiopathic hypercalciuria.

BACKGROUND: Patients with idiopathic hypercalciuria are predisposed to osteoporosis despite their high enteral calcium absorption. Conversely, low calcium absorption has been reported in patients with osteoporosis. Because bone loss occurs earlier in women, this work explores the relationship between bone mineral density (BMD) and calcium absorption in premenopausal and postmenopausal hypercalciuric stone-forming women. METHODS: BMD and intestinal calcium absorption were compared in 64 hypercalciuric and 42 normocalciuric calcium stone-forming women. Calcium absorption was assessed by using strontium as a surrogate marker for calcium. Strontium was administered to patients as an oral load, then measured in blood to calculate absorption after 60 minutes. Femoral and lumbar-spine BMD were measured by dual-energy x-ray absorptiometry. RESULTS: Strontium absorption was significantly increased in hypercalciuric stone formers, whereas BMD z score was decreased in hypercalciuric patients at the lumbar spine, but not the femur. The increase in strontium absorption was detected in both postmenopausal (n = 29) and premenopausal (n = 35) hypercalciuric patients. The decrease in lumbar-spine BMD was confirmed in postmenopausal, but not premenopausal, hypercalciuric patients. Strontium absorption was greater in hypercalciuric patients with a lumbar-spine BMD z score of -2 or less (n = 10) than in those with a score greater than -2 (n = 54). Multiple stepwise regression showed that lumbar-spine BMD was related negatively to intestinal strontium absorption and age in hypercalciuric patients. CONCLUSION: Results of the strontium absorption test suggest that the increase in calcium absorption is associated with a decrease in lumbar-spine BMD in hypercalciuric stone-forming women. Hypercalciuric stone-forming women with high calcium intestinal absorption denote a group of patients predisposed to loss of bone mass.

Absorptiometry, Photon↗
PubMed2003

Genetic polymorphism of the renin-angiotensin-aldosterone system and arterial hypertension in the Italian population: the GENIPER Project.

OBJECTIVE: To detect the association of single polymorphisms of the renin-angiotensin-aldosterone system (RAAS), or different combinations thereof, with hypertension. DESIGN AND METHODS: The GENIPER database is the result of a collaborative effort of 13 Italian research centres to collect genomic DNA in subjects well characterized in terms of blood pressure status. A total of 2461 subjects (normotensive = 611; hypertensive = 1850) were selected and genotyped for the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) T/C704, angiotensin receptor type 1 (AT1) A/C1166 and aldosterone synthase (ALDO) T/C-344 genetic variants. RESULTS: Allele frequencies were homogeneous over the Italian territory, with the relevant exception of the ACE I/D, the D allele being significantly less frequent in the northern region (61%) than in the rest of the country (67%; P < 0.0001). When comparing allele and genotype distributions in normotensives and hypertensives, the latter presented a small but statistically significant increase of the C allele of AGT T/C704, the A allele of AT1 A/C1166 and the T allele of ALDO T/C-344 polymorphisms (P = 0.018, P = 0.037 and P = 0.015, respectively), with similar trends all over the country. A step-wise logistic regression analysis confirmed these findings, by entering in the model as independent predictors of blood pressure status of AGT T/C704 (P = 0.013), ALDO T/C-344 (P = 0.032) and AT1 A/C1166 polymorphisms (P = 0.075), but not ACE I/D (P = 0.996). We also found some evidence of an additive effect of individual genetic variants of the RAAS, modulating at different levels the same functional pathway, on the risk of developing hypertension, but no synergistic interaction was observed. CONCLUSIONS: Our results suggest that some allelic variants of RAAS genes carry a small but identifiable risk of developing arterial hypertension.

Databases, Genetic↗
PubMed2002

Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients.

Calcium-sensing receptor (CaSR) is a plasma membrane protein that regulates tubular reabsorption of Ca. To establish its role in idiopathic hypercalciuria, the association of urinary Ca excretion with the polymorphisms of CASR gene has been studied in healthy subjects and in hypercalciuric and normocalciuric Ca stone formers. CASR exon 7 single nucleotide polymorphisms (SNP), G/T at codon 986, G/A at codon 990, and C/G at codon 1011, were evaluated by PCR amplification and direct sequencing in 97 normocalciuric stone formers, 134 hypercalciuric stone formers, and 101 normocalciuric healthy controls. Four haplotypes were defined on the basis of CASR gene SNP: haplotype 1 was characterized by the most frequent sequence; haplotypes 2, 3, or 4 by the presence of a single polymorphic variant at codon 986, 990, or 1011, respectively. The relative risk of hypercalciuria was calculated with multinomial logistic regression and was significantly increased only in individuals carrying haplotype 3 (Odds ratio, 13.0 [95% confidence interval, 1.7 to 99.4]). Accordingly, Ca excretion was higher in subjects bearing haplotype 3, whereas those bearing haplotype 2 showed a slight increase of plasma Ca concentration. Multiple regression analysis showed that haplotype 3 explained 4.1% of the total variance of Ca excretion and 12.6% of the variance explained by the variables considered in the study. In conclusion, CASR gene could be a component of the complex genetic background regulating Ca excretion. Arg990Gly polymorphism could facilitate activation of CaSR and increase Ca excretion and susceptibility to idiopathic hypercalciuria.

Calcium↗
PubMed2002

alpha-Adducin 460Trp allele is associated with erythrocyte Na transport rate in North Sardinian primary hypertensives.

Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if alpha-adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P<0.0001), whereas intracellular Na concentration was lower (P<0.0001) in patients carrying one or two 460Trp alleles. Such behavior was mirrored by opposite changes of intracellular Na concentration. Plasma renin activity and blood pressure response to diuretic treatment, on the other hand, showed a weaker association with the sodium transport rate. In conclusion, our findings are consistent with the hypothesis that the Gly460Trp alpha-adducin polymorphism may affect renal Na handling through an alteration in ion transport across the cell membrane mirrored by erythrocytes. These results may also have clinical relevance because the Gly460Trp alpha-adducin polymorphism may explain, at least in part, the variability of blood pressure response to diuretics in primary hypertensive patients.

Alleles↗