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J Rossert

Publications and source records attributed to J Rossert.

At least 19 recordsLinked to original sources
PubMed2001

delta Ef1 binds to a far upstream sequence of the mouse pro-alpha 1(I) collagen gene and represses its expression in osteoblasts.

The transcription of type I collagen genes is tightly regulated, but few cis-acting elements have been identified that can modulate the levels of expression of these genes. Generation of transgenic mice harboring various segments of the mouse pro-alpha1(I) collagen promoter led us to suspect that a repressor element was located between -10.5 and -17 kilobase pairs. Stable and transient transfection experiments in ROS17/2.8 osteoblastic cells confirmed the existence of such a repressor element at about -14 kilobase pairs and showed that it consisted in an almost perfect three-time repeat of a 41-base pair sequence. This element, which we named COIN-1, contains three E2-boxes, and a point mutation in at least two of them completely abolished its repressor effect. In gel shift assays, COIN-1 bound a DNA-binding protein named delta EF1/ZEB-1, and mutations that abolished the repressor effect of COIN-1 also suppressed the binding of delta EF1. We also showed that the repressor effect of COIN-1 was not mediated by chromatin compaction. Furthermore, overexpression of delta EF1 in ROS17/2.8 osteoblastic cells enhanced the inhibitory effect of COIN-1 in a dose-dependent manner and repressed the expression of the pro-alpha 1(I) collagen gene. Thus, delta EF1 appears to repress the expression of the mouse pro-alpha 1(I) collagen gene, through its binding to COIN-1.

Animals↗
PubMed2001

[How to slow the progression of chronic renal insufficiency].

In patients with chronic renal failure, three kinds of treatments can slow the progression of renal insufficiency: optimal control of blood pressure; use of converting enzyme inhibitors; low-protein diet. The MDRD study strongly suggests that blood pressure should not be higher than 130/85 mmHg in patients with chronic renal failure, and than 125/75 mmHg in patients with chronic renal failure and proteinuria above 1 g/d. Converting enzyme inhibitors have been shown to be beneficial to patients with IDDM and either microalbuminuria or overt diabetic nephropathy and to patients with chronic renal failure and proteinuria above 1 g/d. A diet containing less than 1 g/kg/d of proteins should be prescribed to patients with chronic renal failure, and this protein content should be lowered to 0.75 g/kg/d (or to 0.60 g/kg/j in some cases) when creatinine clearance falls below 25 mL/min.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets.

The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.

Animals↗
PubMed2001

Blocking sp1 transcription factor broadly inhibits extracellular matrix gene expression in vitro and in vivo: implications for the treatment of tissue fibrosis.

Fibrosis is a consequence of injury characterized by accumulation of excess collagen and other extracellular matrix components, resulting in the destruction of normal tissue architecture and loss of function. Sp1 was originally described as a ubiquitous transcription factor. It is involved in the basal expression of extracellular matrix genes and may, therefore, be important in fibrotic processes. To evaluate the effect of Sp1 blockade on the expression of extracellular matrix genes, clones of NIH 3T3 fibroblasts stably transfected with an anti-sense Sp1 expression vector. Simultaneously reduced expression of several extracellular matrix genes as compared with mock-transfected clones was noted using differential hybridization of cDNA microarrays, without significant alteration in cell growth. Transfection of human dermal fibroblasts with several extracellular matrix gene (COL1A1, COL1A2, COL3A1, COL5A2, COL7A1, TIMP-1, and decorin) promoter/reporter constructs demonstrated that anti-sense Sp1-induced reduction of extracellular matrix gene mRNA steady-state levels results from transcriptional repression, consistent with the role of Sp1 as a transcription factor. Decoy Sp1 binding oligonucleotides inhibited COL1A2 promoter activity both in cultured fibroblasts and in vivo, in the skin of transgenic mice, which have integrated a mouse COL1A2 promoter/luciferase reporter gene construct. These results indicate that targeting Sp1 efficiently blocks extracellular matrix gene expression, and suggest that such an approach may represent an interesting therapeutic alternative toward the treatment of fibrotic disorders.

3T3 Cells↗
PubMed2001

Upper extremity digital subtraction venography with gadoterate meglumine before fistula creation for hemodialysis.

BACKGROUND: The purpose of this study was to evaluate the feasibility, safety, and potential role of gadoterate meglumine (Gd-DOTA) as a contrast agent for upper extremity venography before the creation of an arteriovenous fistula (AVF) for nondialyzed renal insufficiency patients. METHODS: Over a 16-month period, 50 venographies were performed on end-stage renal insufficiency patients, using Gd-DOTA as a contrast agent on a high-resolution digital subtraction angiography system. Three sequences were performed on forearm, arm, and chest at 3 mL/sec for a total of 35 mL of Gd-DOTA. Examinations were reviewed by two radiologists for diagnostic and opacification quality. Tolerance was evaluated on the evolution of serum creatinine levels and occurrence of pain during injection. RESULTS: Good interobserver correlation was obtained in evaluating the feasibility of AVF creation by vein segment (0.64 < kappa < 0.88) and in relationship to opacification quality (0.62 to 0.87). No deterioration in renal function (creatinine level before and after) or pain was observed. Twenty-six patients underwent surgical creation of brachiobasilic (N = 8), brachiocephalic (N = 8), radiocephalic (N = 8), and cubitocephalic (N = 1) fistulas or insertion of a polytetrafluoroethylene (PTFE) graft (N = 1). Seventeen were awaiting AVF or were on peritoneal dialysis. Two died before surgery for reasons unconnected with the venography. CONCLUSIONS: Venography with Gd-DOTA is an effective and safe technique in planning AVFs for renal insufficiency patients.

Adult↗
PubMed2000

Abnormal expression of glomerular basement membrane laminins in membranous glomerulonephritis.

BACKGROUND: Proteinuria associated with glomerular diseases is secondary to alterations of the charge-selective and/or size-selective properties of the glomerular basement membrane (GBM), but molecular alterations that are responsible for these functional changes are still poorly understood. Analysis of mice harbouring a null mutation in the gene encoding the beta 2 chain of laminin has suggested that the presence of abnormal laminin chains within the GBM can be responsible for proteinuria. METHODS: We have investigated whether abnormal laminin ss chains could be detected by immunohistochemistry within the GBM of patients with proteinuria and minimal change disease (five patients), focal and segmental glomerulosclerosis (five patients), or primary membranous glomerulonephritis (10 patients). Three patients with mesangiocapillary glomerulonephritis and three patients with IgA nephropathy were also studied as controls. RESULTS: We showed that the GBM of all 10 patients with membranous glomerulonephritis, but not of patients with other glomerulopathies, contained laminin beta 1, which is normally expressed only during metanephros development. The re-expression of the beta 1 chain of laminin was not associated with that of the embryonic alpha 1 chain of type IV collagen, or with the loss of expression of vimentin and synaptopodin, two markers of differentiated podocytes. CONCLUSIONS: The presence of new laminin isoforms within the GBM of patients with membranous glomerulonephritis could play a role in the occurrence of proteinuria, by modifying either the sieving properties of the GBM or the interactions between podocytes and the GBM.

Adult↗
PubMed2000

Regulation of type I collagen genes expression.

Type I collagen is the major component of many extracellular matrices, and its accumulation characterizes most fibrotic processes. It is synthesized by a small number of discrete cell types, including fibroblasts, osteoblasts and odontoblasts. Analysis of transgenic mice harbouring different segments of the promoters of the mouse pro-alpha1 (I) and pro-alpha2 (I) genes has led to the conclusion that this tissue-specific expression is controlled by different cis-acting elements which are responsible for the expression of type I collagen genes in different type I collagen-producing cells. Transacting factors which bind to these different tissue-specific elements are still unknown, but they probably act by modifying the chromatin structure. In fibroblastic cells, various soluble molecules can modulate the transcription of type I collagen genes. Analysis of the pro-alpha1 (I) and pro-alpha2 (I) proximal promoters has led to the identification of different cis-acting elements which can modulate the expression of reporter genes, in transfection experiments. Among these cis-acting elements, a sequence located between -378 and -183 bp in the human pro-alpha2 (I) promoter appears to mediate the transcriptional effects of transforming growth factor-beta. It binds a large multimeric complex which contains Sp1, as well as AP1 and other DNA-binding proteins which have not yet been identified.

Animals↗
PubMed2000

Identification of a short cis-acting element in the human vasopressin type 2 receptor gene which confers high-level expression of a reporter gene specifically in collecting duct cells.

In the kidney, water reabsorption is mainly regulated by the binding of arginine vasopressin to vasopressin type 2 (V2) receptors. These receptors are expressed selectively in principal cells of the collecting ducts. To identify molecular mechanisms responsible for the cell-specific expression of the V2 receptor, we have analyzed the proximal promoter of the corresponding gene. We report the identification of a 33-bp enhancer [collecting duct tissue-specific element 1 (CSE1)] that induced high levels of expression of the luciferase reporter gene in three collecting duct cell lines, but not in other renal cell lines. In gel shift assays, CSE1 bound a DNA-binding protein expressed selectively in collecting duct cell lines, and a 7-bp mutation, which abolished the activity of CSE1 in transient transfection experiments, also abolished the binding of this protein. Furthermore, decoy experiments performed using CSE1 showed that this sequence was involved not only in the expression of a construct containing 4.2 kb of the V2 receptor proximal promoter, but also in the expression of the endogenous V2 receptor gene. CSE1 appears to act mostly by counteracting the inhibitory effects of a strong ubiquitous repressor element that we called CIE1. Collectively, these results identify the first functional collecting duct-specific cis-acting element.

3T3 Cells↗
PubMed2000

Evaluation of FDG uptake by renal malignancies (primary tumor or metastases) using a coincidence detection gamma camera.

UNLABELLED: The aim of this study was to evaluate the usefulness of FDG scanning using an ordinary gamma camera equipped with coincidence detection (CDET) for 2 renal cancer indications: characterization and staging of renal masses before nephrectomy and search for recurrence after nephrectomy. METHODS: Between September 1997 and June 1998, a whole-body scan and at least 1 tomoscintigram were obtained on 23 occasions in 22 patients (fasting for at least 6 h) using a Prism XP 2000 CDET gamma camera; scanning was begun 45 min after intravenous injection of 150-250 MBq FDG. RESULTS: Postoperative histologic evidence was obtained from 13 of 16 patients who underwent FDG using a CDET gamma camera before renal surgery; 4 renal masses did not accumulate FDG (3 true-negatives, 1 false-negative), whereas 9 renal tumors accumulated FDG (8 true-positives, 1 false-positive). In the other 3 patients, only 1 extrarenal site of FDG uptake was checked and confirmed on histologic examination: a bone metastasis from renal cell carcinoma in 2 cases and lymph node metastasis from a squamous cell carcinoma (3 true-positives). The primary local and regional staging of the malignant renal tumors was accurate in the 9 patients who underwent nephrectomy (8 true-negatives, 1 true-positive). The primary distant staging was positive in 1 case (focus in the chest corresponding to a probable true-positive on follow-up). In the 7 examinations performed because of suspected recurrence of renal cell carcinoma several months after nephrectomy, metastases were visualized by FDG in 4 patients, confirmed by biopsy in 2 patients, and confirmed by conventional imaging or follow-up (or both) in 2 patients. The other 3 patients had negative FDG scans, corresponding to probable true-negative results on follow-up. CONCLUSION: FDG using a CDET gamma camera can be used effectively for the staging and restaging of renal tumors and might be useful for characterization of the primary renal tumor in doubtful cases.

Carcinoma, Renal Cell↗
PubMed2000

[Microscopic polyangiitis].

Microscopic polyangiitis is a non-granulomatous necrotizing vasculitis involving small vessels. Clinical manifestations are highly polymorphic, but rapidly progressive glomerulonephritis is one of the most frequent and most severe manifestations of the disease. Biopsy of an affected organ and detection of circulating anti-neutrophil cytoplasmic antibodies (ANCA) are key elements for the positive diagnosis of microscopic polyangiitis. Biopsies can disclose necrotizing vasculitis affecting small vessels, without granulomas and without immune deposits. ANCA are very specific for microscopic polyangiitis, Wegener's granulomatosis and Churg-Strauss syndrome when they are positive by indirect immunofluorescence and are directed against myeloperoxidase or proteinase 3. Such ANCA are found in about 70% of patients with microscopic polyangiitis. Treatment of severe forms of microscopic polyangiitis is based on the administration of pulse methylprednisolone, oral corticosteroids and cyclophosphamide. In the mildest forms of the disease, one can probably try either to competely avoid using immunosuppressive drugs, or to replace cyclophosphamide with azathioprine. Treatment induces a complete remission of the disease in more than 90% of cases, but about 30% of the patients will experience a relapse, and progressive worsening of renal function can occur in patients with severe chronic renal failure.

Humans↗
PubMed2000

Growth factors, cytokines, and renal fibrosis during the course of diabetic nephropathy.

Diabetic nephropathy is characterised by a progressive accumulation of extracellular matrix within the glomerular mesangium and the interstitium. The pathogenesis of this fibrotic process is still poorly understood, but in vitro and in vivo data suggest that TGF-B plays a key role. Local overproduction of TGF-B could be secondary to a synthesis of diacylglycerol, polyols, or glucosamines. It may also be secondary to an accumulation of advanced glycosylation end-products which modify the functions of neighbouring cells. Moreover, clinical as well as experimental data for TGF-B suggest that angiotensin II has a profibrotic effect; and it has been clearly demonstrated that angiotensin-converting enzyme inhibitors have a beneficial effect in patients with insulin-dependent diabetes mellitus. Other molecules such as endothelin-1, lipid peroxidation products, or IGF-1 may also play a role in this fibrotic process. Finally, heavy proteinuria secondary to glomerular lesions enhances the accumulation of extracellular matrix within the interstitium, probably through modifications of tubular cell functions, thereby inducing the release of pro-inflammatory and profibrotic molecules.

Animals↗
PubMed1998

MPO-ANCA necrotizing glomerulonephritis related to rheumatoid arthritis.

Two patients with rheumatoid arthritis (RA) developed necrotizing crescentic glomerulonephritis with high titers of anti-myeloperoxidase antibodies (MPO) in the absence of overt extrarenal vasculitis. We therefore suggest that in some patients with RA, MPO-ANCA necrotizing glomerulonephritis (GN) may occur as a kidney-limited form of rheumatoid vasculitis, and that RA should be added to the list of diseases potentially associated with necrotizing GN with anti-MPO antibodies. These observations also point out the importance of repeatedly evaluating titers of anti-MPO antibodies in the course of RA, especially if renal impairment or abnormal urinary sediment are present.

Aged↗
PubMed1998

Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients.

We analyzed the clinical and laboratory characteristics of 50 patients with catastrophic antiphospholipid syndrome (APS) (5 from our clinics and 45 from a MEDLINE computer-assisted review of the literature from 1992 through 1996). Thirty-three (66%) patients were female and 17 (34%) were male. Twenty-eight (56%) patients had primary APS, 15 (30%) had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and 1 (2%) had rheumatoid arthritis. Mean age of patients in this series was 38 +/- 14 years (range, 11-74 yr). Three (6%) patients developed the clinical picture of catastrophic APS under the age of 15 years, and 11 (22%) were 50 years old or more. In 11 (22%) patients, precipitating factors contributed to the development of catastrophic APS (infections in 3, drugs in 3, minor surgical procedures in 3, anticoagulation withdrawal in 2, and hysterectomy in 1). The presentation of the acute multi-organ failure was usually complex, involving multiple organs simultaneously or in a very short period of time. The majority of patients manifested microangiopathy--that is, occlusive vascular disease affecting predominantly small vessels of organs, particularly kidney, lungs, brain, heart, and liver--with a minority of patients experiencing only large vessel occlusions. Thrombocytopenia was reported in 34 (68%) patients, hemolytic anemia in 13 (26%), disseminated intravascular coagulation in 14 (28%), and schistocytes in 7 (14%). The following antibodies were detected: lupus anticoagulant (94%), anticardiolipin antibodies (94%), anti-dsDNA (87% of patients with SLE), antinuclear antibodies (58%), anti-Ro/SS-A (8%), anti-RNP (8%), and anti-La/SS-B (2%). Anticoagulation was used in 70% of the patients, steroids in 70%, plasmapheresis in 40%, cyclophosphamide in 34%, intravenous gammaglobulins in 16%, and splenectomy in 4%. Most patients, however, received a combination of nonsurgical therapies. Death occurred in 25 of the 50 (50%) patients. In most, cardiac problems seemed to be the major cause of death. In several of these, respiratory failure was also present, usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Among the 20 patients who received the combination of anticoagulation, steroids, and plasmapheresis or intravenous gammaglobulins, recovery occurred in 14 (70%) patients. The use of ancrod and defibrotide appeared to be effective in the 2 respective patients in whom they were used.

Adolescent↗