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G Choukroun

Publications and source records attributed to G Choukroun.

At least 19 recordsLinked to original sources
PubMed1999

Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH(2)-terminal kinases.

Cardiac hypertrophy often presages the development of heart failure. Numerous cytosolic signaling pathways have been implicated in the hypertrophic response in cardiomyocytes in culture, but their roles in the hypertrophic response to physiologically relevant stimuli in vivo is unclear. We previously reported that adenovirus-mediated gene transfer of SEK-1(KR), a dominant inhibitory mutant of the immediate upstream activator of the stress-activated protein kinases (SAPKs), abrogates the hypertrophic response of neonatal rat cardiomyocytes to endothelin-1 in culture. We now report that gene transfer of SEK-1(KR) to the adult rat heart blocks SAPK activation by pressure overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo. Furthermore, gene transfer of SEK-1(KR) inhibited pressure overload-induced cardiac hypertrophy, as determined by echocardiography and several postmortem measures including left ventricular (LV) wall thickness, the ratio of LV weight to body weight, cardiomyocyte diameter, and inhibition of atrial natriuretic factor expression. Our data suggest that the SAPKs are critical regulators of cardiac hypertrophy in vivo, and therefore may serve as novel drug targets in the treatment of hypertrophy and heart failure.

Adenoviridae↗
PubMed1999

Signaling pathways mediating the response to hypertrophic stress in the heart.

Cardiac hypertrophy is an increase in the mass of the heart. It is a major risk factor for the development of myocardial infarction and congestive heart failure, diseases that afflict millions of patients worldwide. Hypertrophy can be caused by intrinsic defects of the proteins of the contractile apparatus of the heart, or by extrinsic stimuli such as hypertension. In this review, we will focus on the cytosolic signal transduction pathways that mediate the hypertrophic response to extrinsic stimuli. Although a large number of signaling molecules have been implicated in the hypertrophic response, we will review data that, we believe, suggest there may be only a few molecules that serve as signaling funnels through which many hypertrophic signals must pass on their way to the nucleus. These include the stress response protein kinases (the stress-activated protein kinases or SAPKs, and, possibly, the p38 kinases) and calcineurin. These molecules have as their primary targets transcription factors, many of which have been implicated in the complex yet stereotypic genetic response to hypertrophic stress. In most cases, it is not possible at present to complete the link from hypertrophic stimulus through a specific signaling molecule and a specific transcription factor to the induction of a specific gene that initiates a particular biologic response. We will attempt to identify some of the most important areas where major questions remain in the hopes of stimulating further research into this major cause of death and disability.

Animals↗
PubMed1998

Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy.

The signal transduction pathways governing the hypertrophic response of cardiomyocytes are not well defined. Constitutive activation of the stress-activated protein kinase (SAPK) family of mitogen-activated protein (MAP) kinases or another stress-response MAP kinase, p38, by overexpression of activated mutants of various components of the pathways is sufficient to induce a hypertrophic response in cardiomyocytes, but it is not clear what role these pathways play in the response to physiologically relevant hypertrophic stimuli. To determine the role of the SAPKs in the hypertrophic response, we used adenovirus-mediated gene transfer of SAPK/ERK kinase-1 (KR) [SEK-1(KR)], a dominant inhibitory mutant of SEK-1, the immediate upstream activator of the SAPKs, to block signal transmission down the SAPK pathway in response to the potent hypertrophic agent, endothelin-1 (ET-1). SEK-1(KR) completely inhibited ET-1-induced SAPK activation without affecting activation of the other MAP kinases implicated in the hypertrophic response, p38 and extracellular signal-regulated protein kinases (ERK)-1/ERK-2. Expression of SEK-1(KR) markedly inhibited the ET-1-induced increase in protein synthesis. In contrast, the MAPK/ERK kinase inhibitor, PD98059, which blocks ERK activation, and the p38 inhibitor, SB203580, had no effect on ET-1-induced protein synthesis. ET-1 also induced a significant increase in atrial natriuretic factor mRNA expression as well as in the percentage of cells with highly organized sarcomeres, responses which were also blocked by expression of SEK-1(KR). In summary, inhibiting activation of the SAPK pathway abrogated the hypertrophic response to ET-1. These data are the first demonstration that the SAPKs are necessary for the development of agonist-induced cardiomyocyte hypertrophy, and suggest that in response to ET-1, they transduce critical signals governing the hypertrophic response.

Adenoviridae↗
PubMed1998

Early glomerular dysfunction in patients with sickle cell anemia.

The purpose of this study was to analyze the determinants of glomerular filtration in nonnephrotic young adult patients with sickle cell anemia (SCA). We prospectively screened 14 patients with homozygous SCA who had normal plasma creatinine concentrations and normal or moderately elevated albuminuria (< 1 g/d). Inulin, paraaminohippuric acid, and dextran clearances were evaluated and compared with values obtained from a control group (age-matched healthy volunteers). SCA patients had a significantly higher glomerular filtration rate and effective renal plasma flow than controls (146 +/- 9 mL/min/1.73 m2 v 120 +/- 3 mL/min/1.73 m2 [P < 0.01] and 1,052 +/- 69 mL/min/1.73 m2 v 709 +/- 38 mL/min/1.73 m2 [P < 0.001], respectively). We found no correlation between glomerular filtration rate or effective renal plasma flow and hematocrit. Fractional clearance of neutral dextran was significantly elevated in SCA patients for all radii between 3.4 and 5.4 nm. Theoretical analysis of dextran transport through a heteroporous membrane model revealed a slight increase in the mean radius (ro) of restrictive pores (5.68 nm v5.50 nm; P < .001) and no significant difference in shunt pathway (omega o) values. Among the other hemodynamic parameters, the most significant change was a dramatic increase in ultrafiltration coefficient (41.3 +/- 3.6 mL/mm Hg/min/1.73 m2 v 25.1 +/- 2.6 mL/mm Hg/min/1.73 m2; P < 0.001). Our results suggest that hyperfiltration in SCA patients is associated not only with enhanced renal perfusion but also with an alteration in glomerular permeability and with an increase in Kf. This change in Kf is fully in agreement with the large increase in glomerular area previously described in SCA patients. Based on our results and those of previous morphologic studies, we propose that enhanced transglomerular trafficking of macromolecules associated with podocyte stretch lesions (defects) induced by glomerular hypertrophy may play a role in the genesis of this particular form of focal segmental glomerulosclerosis, which is associated with SCA.

Adult↗
PubMed1997

Low urine flow reduces the capacity to excrete a sodium load in humans.

Recent studies in rats suggest that vasopressin and the resulting urinary concentrating activity reduce the capacity of the kidney to excrete sodium. The present study investigates the influence of the level of hydration on the excretion of a sodium load in humans. Eight healthy male volunteers (18-35 yr) were studied twice, in random order, under either low (LowH) or high (HighH) hydration. They drank throughout the study either 0.25 (LowH) or 2.0 ml water/kg body wt (HighH) every 30 min. After 1 h equilibration, urine was collected for 2 h before (basal) and 10 h after the NaCl load (5 g NaCl in 250 ml, infused intravenously over 30 min). Differences in excretory patterns between LowH and HighH were mostly confined to the first 4 h after the load. The increase in Na excretion after the load was more intense under HighH than under LowH (+ 10.9 +/- 2.6 vs. + 5.8 +/- 2.7 mmol/h in the first 4 postload h; P < 0.001). Under HighH, urine flow rate (V) increased markedly (+ 41%), with little change in urinary Na concentration (UNa), whereas under LowH, V declined slightly and UNa rose significantly (+ 33%). The capacity to raise UNa seemed to reach a maximum at approximately 280 mM. In both conditions, the changes in UNa observed after the load were positively correlated with basal UNa. After the load, urea excretion increased under HighH and decreased under LowH, whereas K excretion was unaffected in either condition. These results show that sodium excretion is facilitated by an abundant water supply. The less efficient sodium excretion occurring at low V is probably due to the influence of vasopressin on water, urea, and sodium movements across the collecting ducts. These observations suggest that, in everyday life, a low water intake could limit the capacity to excrete sodium. Whether this could contribute to salt-sensitive hypertension remains to be evaluated.

Adult↗
PubMed1997

Pregnancy in women with impaired renal function.

The outcome and consequences of pregnancy in women with impaired renal function are still debated. To assess the benefit of recent advances in coordinated obstetrical and nephrologic management, we analyzed fetal and maternal outcome of 43 pregnancies in 30 women with various types of primary renal disease and moderate to severe renal failure at conception defined by serum creatinine concentration (Scr) ranging from 0.11 to 0.49 mmol/l. All pregnancies took place during the 20-year period from 1975 through 1994 and were prospectively followed jointly by our Nephrology Unit and Obstetric and Neonatology Units of University Hospitals. Of the 43 pregnancies (45 fetuses), 13 ended in fetal death (including 5 first-trimester abortions and 8 fetal deaths beyond the 20th gestational week). There were 32 live births, a success rate of 82% not considering first-trimester abortions. Successful pregnancies were significantly more frequent in the last decade than in the preceding one (91 vs 65%, p = 0.05). Overall live birth rate was higher in pregnancies started with Scr < 0.20 mmol/l than in those with Scr > 0.20 mmol/l (80% vs 53%, p = 0.02). The upper preconception Scr value associated with a successful fetal outcome was 0.27 mmol/l. Hypertension was the major factor of fetal prognosis, as the relative risk of fetal loss was 10.6 times higher when hypertension was present at conception or early in pregnancy than when blood pressure was spontaneously normal or well-controlled by therapy. An accelerated course toward end-stage renal failure was observed in 7 patients (23%), all of whom had severe hypertension and heavy proteinuria at conception. We conclude that fetal outcome in patients with impaired renal function has been improved in recent years, due to advances in obstetrics and neonatology, improved blood pressure control and close co-operation between nephrologists and obstetricians, but that a risk of fetal loss and of accelerated deterioration of maternal renal disease still persists when Ccr at conception is lower than 25-30 ml/ min/1.73 m2.

Adult↗
PubMed1996

Pregnancy in women with reflux nephropathy.

Reflux nephropathy is one of the most prevalent renal diseases and a leading cause of chronic renal failure in women-of childbearing age. To evaluate the issue and possible complications of pregnancy in women with reflux nephropathy, we retrospectively analyzed fetal and maternal outcome in 158 women who had 375 pregnancies between 1965 and 1994. The overall fetal death rate was 10.2% and tended to decrease in the 1985 to 1994 decade as compared to the preceding period (8.4% vs. 12.6%). The relative risk of fetal death was 4.8 times greater hypertension was present at conception than in normotensive patients. Fetal death rate was also higher in patients with impaired renal function that in those with serum creatinine < 0.11 mmol/liter at conception (36.7% vs. 7.7%, P < 0.0001). Urinary tract infection accounted for frequent morbidity but seldom resulted in fetal mortality. Maternal renal disease was unaffected by pregnancy, excepted for 4 of the 21 patients with pre-existing renal failure who exhibited an irreversibly accelerated course after pregnancy. We conclude that pregnancy is essentially successful and uneventful in patients diagnosed with reflux nephropathy who have normal blood pressure and preserved renal function, whereas the fetal prognosis is more compromised and there is a risk of accelerated progression of maternal renal disease when serum creatinine concentration is in excess of 0.22 mmol/ liter. This suggests that women with reflux nephropathy should preferably conceive before having reached that stage of renal failure.

Adolescent↗
PubMed1995

Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) frequently leads to end-stage renal failure (ESRF) in the sixth decade of life, but considerable heterogeneity exists in the rate of progression of renal failure. The respective contribution of genetic factors and of potentially amendable factors, such as blood pressure control or protein intake limitation, on the rate of progression in ADPKD patients is still debated. To evaluate the role of factors influencing the rate of progression of renal failure in ADPKD, we retrospectively analyzed the annual rate of decline of creatinine clearance (Ccr) in 109 ADPKD patients followed from the time a Ccr value of 30 to 50 mL per min/1.73 m2 was measured until ESRD and need for hemodialysis (Study A), and in 48 undialyzed ADPKD patients followed for at least 4 yr from the time a Ccr value of 50 to 60 mL per min/1.73 m2 was measured (Study B). In Study A, the decline in Ccr (delta Ccr) (mean +/- SE) was 5.8 +/- 0.2 mL per min/1.73 m2 per year in the whole series, and was lower in females than in males (5.0 +/- 0.2 versus 6.4 +/- 0.2, P < 0.001). Accordingly, ESRF was reached at a later age in female patients (55.1 +/- 1.2 versus 50.6 +/- 1.2 yr, P < 0.01). The age at ESRF in male patients was lower when the disease was transmitted by mother than by father (46.3 +/- 1.9 versus 54.1 +/- 1.8 yr, P < 0.01), whereas no significant effect of the gender of the affected parent was apparent in female patients. By regression analysis, there was a positive but weak relationship between delta Ccr and mean arterial pressure (average value during follow-up, 107 +/- 1 mm Hg, r = 0.224, P < 0.05) but not with dietary protein intake (mean value in follow-up, 0.87 +/- 0.03 g/kg per day, r = 0.10, P = 0.33) nor with proteinuria at baseline, which was lower than 0.3 g/day in 104 cases (r = 0.10, P = 0.28). There was a negative relationship between age at ESRF and delta Ccr (r = 0.245, P < 0.05), with a later and slower progression in older subjects. In Study B, the mean decline in renal function during follow-up was 5.3 +/- 0.4 mL/min/1.73 m2 per year, a value close to that observed in Study A. By multiple regression analysis of the overall population (studies A and B combined), only MAP, age and gender were independent predictive factors of delta Ccr but all studied parameters taken together accounted for at best 20% of delta Ccr variation. We conclude that the rate of progression of renal failure in ADPKD patients is mainly determined by gene expression, with female gender and older age associated with a slower progression, whereas blood pressure control, but not protein intake, exerts a limited beneficial influence on the rate of progression in patients with advanced polycystic kidney disease who already have significant renal insufficiency.

Adult↗