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Biomedical subjects

Jean-Claude Dussaule

Publications and source records attributed to Jean-Claude Dussaule.

6 recordsLinked to original sources
PubMed2003

Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases.

Renal fibrosis is one of the major complications associated with the development of hypertension. The objective of the present study was to determine whether and by which mechanisms treatment with AT1 receptor antagonists makes possible the regression of renal vascular and glomerular fibrosis. Experiments were performed in the hypertensive model of nitric oxide (NO) deficiency in rats. After 4 wk of hypertension, mortality rates averaged 20%; the surviving animals displayed a decline of renal function (urine protein/creatinine, 1.89 +/- 0.63 versus 0.24 +/- 0.03 mg/mmol; creatininemia, 110 +/- 14 versus 38 +/- 2 mmol/L in hypertensive animals and control, respectively; P < 0.01) and an exaggerated gene and protein expression of TGF-beta, collagen I, and collagen IV (P < 0.001) within the renal vasculature associated with the development of glomerulosclerosis (sclerotic index, 2.26 +/- 0.29 versus 0.12 +/- 0.04; P < 0.001). In addition, activities of matrix metalloproteinases 2 and 9 were increased twofold in renal vessels and glomeruli (P < 0.01). Afterwards, losartan, an antagonist of angiotensin receptor type I, or hydralazine were administered in subgroups of hypertensive animals. After 1 wk of angiotensin II antagonism, collagen I, collagen IV, and TGF-beta gene and protein expressions were decreased and glomerulosclerosis was less marked (sclerotic index 1.04 +/- 0.45), whereas activities of metalloproteinases remained twofold higher than controls (P < 0.01). Hydralazine failed to improve renal function despite a similar degree of systolic pressure decrease. After 4 wk of losartan, the renal functional and histologic parameters were completely normalized, whereas they remained damaged in the hypertensive animals in which the mortality rate reached 85%. These data suggest that the progression of renal vascular fibrosis is a reversible process, at least in the NO deficiency model. The mechanism of the regression appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade.

Angiotensin Receptor Antagonists↗
PubMed2002

Epidermal growth factor receptor trans-activation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice.

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension-associated vascular fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis that activation of the epidermal growth factor (EGF) receptor pathway mediates these events. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Endothelin induced a rapid phosphorylation of the mitogen-activated protein kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated aortas. This effect of endothelin was totally inhibited by an endothelin receptor antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor phosphorylation decreased the endothelin-induced pressor effect in isolated aortic rings and in anesthetized animals in vivo. In addition, the endothelin-induced increase of blood pressure was blunted in the waved-2 mice, a strain expressing functionally impaired EGF receptors. Our results provide the first evidence that the EGF receptor mediates at least two of the major actions of endothelin in the vascular tissue: contractility and fibrogenesis.

Animals↗
PubMed2002

Renal and vascular effects of S21402, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase, in healthy subjects with hypovolemia.

OBJECTIVE: To examine the mechanism of action of dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase, also called vasopeptidase inhibitors, we compared the effects of S21402 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido]propionic acid], which belongs to this pharmacologic class, with those of captopril, an ACE inhibitor, on blood pressure, endocrine parameters, and renal in healthy subjects with hypovolemia. METHODS: Ten subjects participated to this double-blind, 2-period, randomized, crossover study. Hypovolemia was induced in these subjects with a 7-day treatment of hydrochlorothiazide. They received a single oral dose of 50 mg captopril or 250 mg S21402 on the last day of diuretic treatment. Blood pressure was measured, and urine and blood samples were collected before and during a 12-hour period after drug administration. RESULTS: The plasma angiotensin II/angiotensin I ratio and aldosterone concentration decreased to the same degree with both drugs, 3 hours after dosing. Compared with captopril, S21402 increased levels of plasma atrial natriuretic peptide (P <.05) and urinary cyclic guanosine monophosphate (P <.001); these increases were the result of inhibition of neutral endopeptidase activity (P <.001). The increase in plasma renin concentration related to ACE inhibition was less marked (P <.001) after S21402 than after captopril. S21402, but not captopril, increased urinary sodium excretion (P <.05), without modifying blood pressure and creatinine clearance, whereas blood pressure transiently fell after captopril administration (P <.05). CONCLUSIONS: In healthy hypovolemic subjects, the vasopeptidase inhibitor S21402 exhibits a natriuretic effect and does not affect blood pressure or glomerular filtration rate. In these conditions, the acute endocrine, vascular, and renal effects of vasopeptidase inhibition differ from those of ACE inhibition.

Adult↗
PubMed2002

[Vasoactive peptides and the development of renal sclerosis: contribution of transgenes].

Vasoactive peptides are implied in the development of renal sclerosis as evidenced by the efficiency of their antagonists in preventing glomerulosclerosis of experimental and human nephropathies. Genetically engineered models provide a new approach to investigate the mechanisms of the renal profibrotic actions of angiotensin II and endothelin. Overexpression of the human angiotensinogen and renin genes in rats induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed in mice. Transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[1]) and made hypertensive by induction of nitric oxide (NO) deficiency were used to study the renal profibrotic actions of vasoactive peptides. In this strain of mice, luciferase activity is an early index of renal fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were deficient in NO. The pharmacological blockade of angiotensin II and endothelin prevented the development of renal sclerosis without modifying blood pressure. Moreover, when the endothelin receptor antagonist was administered after the development of renal fibrosis, preformed glomerulosclerosis partially regressed. Acute administration of vasoactive peptides and TGF-beta in transgenic procol alpha 2[1] mice showed that the angiotensin II activation of collagen I gene requires participation and/or cooperation of endothelin and TGF-beta. Recent data suggest that the profibrotic actions of vasoactive peptides also need the activation of EGF receptor, ERK and rho kinase pathways in renal and vascular cells.

Angiotensin II↗
PubMed2001

Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta.

Hypertension is frequently associated with the development of renal vascular fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-beta (TGF-beta) could be a player in this interaction. Experiments were performed in vivo on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol alpha 2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-beta (also administered intravenously) produced a rapid increase of procol alpha 2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-beta). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-beta.

Angiotensin II↗