PubMed Health⌕ Search

Biomedical subjects

Vivette D'Agati

Publications and source records attributed to Vivette D'Agati.

At least 19 recordsLinked to original sources
PubMed2006

FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis.

Lupus glomerulonephritis is initiated by deposition of IgG-containing immune complexes in renal glomeruli. FcR engagement by immune complexes (IC) is crucial to disease development as uncoupling this pathway in FcRgamma(-/-) abrogates inflammatory responses in (NZB x NZW)F1 mice. To define the roles of FcR-bearing hemopoietic cells and of kidney resident mesangial cells in pathogenesis, (NZB x NZW)F1 bone marrow chimeras were generated. Nephritis developed in (NZB x NZW)F1 mice expressing activating FcRs in hemopoietic cells. Conversely, recipients of FcRgamma(-/-) bone marrow were protected from disease development despite persistent expression of FcRgamma in mesangial cell populations. Thus, activating FcRs on circulating hemopoietic cells, rather than on mesangial cells, are required for IC-mediated pathogenesis in (NZB x NZW)F1. Transgenic FcRgamma(-/-) mice expressing FcRgamma limited to the CD11b+ monocyte/macrophage compartment developed glomerulonephritis in the anti-glomerular basement disease model, whereas nontransgenic FcRgamma(-/-) mice were completely protected. Thus, direct activation of circulating FcR-bearing myeloid cells, including monocytes/macrophages, by glomerular IC deposits is sufficient to initiate inflammatory responses.

Animals↗
PubMed2006

BP1 is a negative modulator of definitive erythropoiesis.

Beta protein 1 (BP1), a human homeotic transcription factor, is expressed during hematopoeisis in the erythroid lineage. To determine the in vivo role of BP1 in erythropoiesis, we have undertaken two complementary approaches using enforced BP1 expression in both transgenic mice and embryonic stem (ES) cells. Despite repeated attempts, only one adult transgenic BP1 founder mouse among 121 mice was obtained. This mouse presumably survived due to transgene mosaicism because the transgene could not be transmitted. This mouse expressed BP1 and displayed splenomegaly, extramedullary erythropoiesis and severe amyloidosis A in the kidney, a phenotype compatible with thalassemia. Consistently, the presence of BP1 transgene in fetuses was associated with paleness and lethality. In ES cells, BP1 expression in primary differentiation appeared to antagonize adult beta-globin expression. In secondary differentiation, BP1 expression reduced significantly beta-globin gene expression in both primitive and definitive erythroid cells, whereas it impaired only the definitive erythroid cell differentiation. These studies showed that BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia.

Amyloidosis↗
PubMed2006

Alloantibodies and the outcome of cadaver kidney allografts.

The role of humoral immunity in causing antibody-mediated rejection (AMR) of organ allografts has been extensively documented. For this reason, negative complement-dependent cytotoxicity (CDC) cross-matches between recipient sera and donor T and B lymphocytes have become a mandatory requirement for cadaveric kidney transplantation. However, the significance of donor-specific antibodies (DSAs) detectable only by flow cytometry (FC) or solid phase assays (SPA) but not CDC is still controversial. We have performed a retrospective analysis of FC cross-matching results in 80 consecutive cadaver kidney allograft recipients. Antibodies against HLA class I and class II antigens were measured by CDC and SPA in sequential samples of sera obtained prior to transplantation. The preoperative cross-match was performed by CDC using magnetically sorted T and B cells from donor spleen. Sera obtained from each patient before and at the time of transplantation were included in the final cross-match. The sample of serum obtained at the time of transplantation was cross-matched retrospectively by FC and analyzed for anti-HLA antibody specificity on high resolution SPA. The actuarial kidney allograft survival at one year was 98%. Two of these eighty patients lost the graft, one due to AMR, the other for reasons unrelated to DSAs. Donor-specific antibodies were detected by FC in 17 of 80 patients, yet only 6 of 17 had an early episode of AMR. This episode was successfully reversed by desensitization therapy using intravenous immunoglobin (IVIG) and plasmapheresis. Flow cytomery cross-matching showed 95% specificity but only 35% sensitivity for prediction of AMR (p = 0.002). There was a significant correlation between high panel reactive antibodies (PRA) and positive FC cross-matching (p = 0 .0001), as well as high PRA and AMR (p = 0.0004 by CDC and 0.0011 by Luminex). Reversible AMR occurred 12-30 days post-transplantation in 8 patients. Of these 8 patients, 3 had no detectable DSAs in spite of C4d positivity, 4 had C4d deposition in conjunction with anti-HLA antibodies, and 1 patient had DSAs (anti-MICA) yet no C4d deposition. We conclude that early initiation of desensitization protocols can prevent transplant failure and that retrospective FC cross-matches may facilitate the diagnosis of AMR. Extensive analysis of patients' sera using a comprehensive set of tests may contribute to early treatment and better understanding of the mechanism underlying humoral rejection.

Cadaver↗
PubMed2005

Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Up to 40% progress to end-stage renal disease (ESRD) over 10-20 years. Currently, treatment is limited. We studied the use of mycophenolate mofetil (MMF) vs placebo in a group of North American IgAN patients at high risk for progressive disease. METHODS: Included were 32 patients aged 18-75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors: (i) male sex; (ii) hypertension >150/90 mmHg or requiring antihypertensive medications; (iii) creatinine clearance, measured by 24 h urine collection, <80 and >20 ml/min at time of enrolment; and (iv) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy. Patients were randomized to either 1 year of MMF, titrated up to a dose of 1000 mg bid, or placebo. Total follow-up was 2 years. All patients received angiotensin inhibition medication. The primary outcome was a 50% increase in baseline serum creatinine (SCr). Secondary outcomes were an increase of 0.5 mg/dl SCr, ESRD and a 50% reduction in proteinuria. RESULTS: The mean baseline SCr was 2.4 mg/dl. No statistically significant differences were observed for any outcome. Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50% increase in SCr (P = 0.4). In both groups, all patients who reached the primary outcome also reached ESRD. Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr (P = 0.7) Only three MMF and two placebo patients had a 50% reduction in 24 h proteinuria. No serious adverse events occurred in either group. CONCLUSION: No benefit was seen in patients who received MMF in this high risk group, probably reflecting the relatively advanced stage of disease of our population. We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency.

Adult↗
PubMed2005

The role of GDNF in patterning the excretory system.

Mesenchymal-epithelial interactions are an important source of information for pattern formation during organogenesis. In the developing excretory system, one of the secreted mesenchymal factors thought to play a critical role in patterning the growth and branching of the epithelial ureteric bud is GDNF. We have tested the requirement for GDNF as a paracrine chemoattractive factor by altering its site of expression during excretory system development. Normally, GDNF is secreted by the metanephric mesenchyme and acts via receptors on the Wolffian duct and ureteric bud epithelium. Misexpression of GDNF in the Wolffian duct and ureteric buds resulted in formation of multiple, ectopic buds, which branched independently of the metanephric mesenchyme. This confirmed the ability of GDNF to induce ureter outgrowth and epithelial branching in vivo. However, in mutant mice lacking endogenous GDNF, kidney development was rescued to a substantial degree by GDNF supplied only by the Wolffian duct and ureteric bud. These results indicate that mesenchymal GDNF is not required as a chemoattractive factor to pattern the growth of the ureteric bud within the developing kidney, and that any positional information provided by the mesenchymal expression of GDNF may provide for renal branching morphogenesis is redundant with other signals.

Animals↗
PubMed2005

Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform.

The receptor tyrosine kinase Ret plays a critical role in the development of the mammalian excretory and enteric nervous systems. Differential splicing of the primary Ret transcript results in the generation of two main isoforms, Ret9 and Ret51, whose C-terminal amino acid tails diverge after tyrosine (Y) 1062. Monoisoformic mice expressing only Ret9 develop normally and are healthy and fertile. In contrast, animals expressing only Ret51 have aganglionosis of the distal gut and hypoplastic kidneys. By generating monoisoformic mice in which Y1062 of Ret9 has been mutated to phenylalanine, we demonstrate that this amino acid has a critical role in Ret9 signaling that is necessary for the development of the kidneys and the enteric nervous system. These findings argue that the distinct activities of Ret9 and Ret51 result from the differential regulation of Y1062 by C-terminal flanking sequences. However, a mutation which places Y1062 of Ret51 in a Ret9 context improves only marginally the ability of Ret51 to support renal and enteric nervous system development. Finally, monoisoformic mice expressing a variant of Ret9 in which a C-terminal PDZ-binding motif was mutated develop normally and are healthy. Our studies identify Y1062 as a critical regulator of Ret9 signaling and suggest that Ret51-specific motifs are likely to inhibit the activity of this isoform.

Alternative Splicing↗
PubMed2005

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.

Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

Acute-Phase Proteins↗
PubMed2005

Receptor for advanced glycation end products and its ligands: a journey from the complications of diabetes to its pathogenesis.

Many studies have suggested that the expression of RAGE (receptor for advanced glycation end products) is upregulated in human tissues susceptible to the long-term complications of diabetes. From the kidneys to the macrovessels of the aorta, RAGE expression is upregulated in a diverse array of cell types, from glomerular epithelial cells (podocytes) to endothelial cells, vascular smooth muscle cells, and inflammatory mononuclear phagocytes and lymphocytes. Although RAGE was first described as a receptor for advanced glycation end products (AGEs), the key finding that RAGE was also a signaling receptor for proinflammatory S100/calgranulins and amphoterin, led to the premise that even in euglycemia, ligand-RAGE interaction propagated inflammatory mechanisms linked to chronic cellular perturbation and tissue injury. Indeed, such considerations suggested that RAGE might even participate in the pathogenesis of type 1 diabetes. Our studies have shown that pharmacological and/or genetic deletion/mutation of the receptor attenuates the development of hyperglycemia in NOD mice; in mice with myriad complications of diabetes, interruption of ligand-RAGE interaction prevents or delays the chronic complications of the disease in both macro- and microvessel structures. Taken together, these findings suggest that RAGE is "at the right place and time" to contribute to the pathogenesis of diabetes and it complications. Studies are in progress to test the premise that antagonism of this interaction is a logical strategy for the prevention and treatment of diabetes.

Animals↗
PubMed2004

CTNNB1 mutations and overexpression of Wnt/beta-catenin target genes in WT1-mutant Wilms' tumors.

Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1.

Cells, Cultured↗
PubMed2004

Reversal of collapsing glomerulopathy in mice with the cyclin-dependent kinase inhibitor CYC202.

Collapsing glomerulopathy (CG) has become an important cause of end-stage renal disease. Whether associated with HIV-1 or other potential etiologies, the pathogenesis of CG converges to induce aberrant proliferation of renal epithelium along the entire nephron. This raises the possibility that targeting cell-cycle progression may be an effective therapeutic strategy for CG. Here, we ask whether the cyclin-dependent kinase (CDK) inhibitor, CYC202 (R-roscovitine), could attenuate or reverse existing renal disease in Tg26 mice, a well characterized HIV-1 transgenic mouse model of CG. Tg26 mice were age and disease matched through analysis of urine (protein/creatinine) to generate 12 treatment pairs covering a range of mild to severe CG. One mouse from each pair received either vehicle or 75 mg/kg of CYC202 every 12 h for 20 d, a dose 20% above that needed to prevent the development of CG. After treatment, urinary, serologic, and histopathologic indices of nephrosis showed reversal of CG in 8 of 12 CYC202-treated mice compared with progression of CG in 10 of 12 vehicle-treated mice, demonstrating a significant therapeutic benefit from CYC202 (P < 0.05). Pharmacokinetic profiles showed that concentrations of CYC202 known to inhibit cell-cycle and transcriptional CDK in vitro were achieved in plasma at efficacious doses. However, amelioration of CG by CYC202 did not correlate with decreases in kidney HIV-1 transgene expression, indicating that suppression of HIV-1 transcription was not a prerequisite for the antiproliferative activity of CYC202. These results demonstrate a novel therapeutic strategy for CG.

Animals↗
PubMed2004

Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli.

The molecular pathogenesis of focal/diffuse proliferative lupus glomerulonephritis was studied by cDNA microarray analysis of gene expression in glomeruli from clinical biopsies. Transcriptional phenotyping of glomeruli isolated by laser-capture microscopy revealed considerable kidney-to-kidney heterogeneity in increased transcript expression, resulting in four main gene clusters that identified the presence of B cells, several myelomonocytic lineages, fibroblast and epithelial cell proliferation, matrix alterations, and expression of type I IFN-inducible genes. Glomerulus-to-glomerulus variation within a kidney was less marked. The myeloid lineage transcripts, characteristic of those found in isolated activated macrophages and myeloid dendritic cells, were widely distributed in all biopsy samples. One major subgroup of the samples expressed fibrosis-related genes that correlated with pathological evidence of glomerulosclerosis; however, decreased expression of TGF-beta1 argued against its role in lupus renal fibrosis. Expression of type I IFN-inducible transcripts by a second subset of samples was associated with reduced expression of fibrosis-related genes and milder pathological features. This pattern of gene expression resembled that exhibited by activated NK cells. A large gene cluster with decreased expression found in all samples included ion channels and transcription factors, indicating a loss-of-function response to the glomerular injury.

Adolescent↗
PubMed2003

Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders.

The glycation and oxidation of proteins/lipids leads to the generation of a new class of biologically active moieties, the advanced glycation endproducts (AGEs). Recent studies have elucidated that carboxymethyllysine (CML) adducts of proteins/lipids are a highly prevalent AGE in vivo. CML-modified adducts are signal transduction ligands of the receptor for AGE (RAGE), a member of the immunoglobulin superfamily. Importantly, CML-modified adducts accumulate in diverse settings. In addition to enhanced formation in settings of high glucose, these adducts form in inflammatory milieu. Studies performed both in vitro and in vivo have suggested that the proinflammatory/tissue destructive consequences of RAGE activation in the diabetic/inflamed environment may be markedly attenuated by blockade of the ligand-RAGE axis. Here, we will summarize the known consequences of RAGE activation in the tissues and highlight novel areas for therapeutic intervention in these disease states.

Animals↗
PubMed2003

Pathologic classification of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin nephropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations.

Disease Progression↗
PubMed2003

Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity.

BACKGROUND: Studies of proliferative lupus nephritis (PLN) suggest that African-Americans have a poorer prognosis than Whites. However, no study has simultaneously examined socio-economic status. We studied rates of progression of PLN among a tri-ethnic population with respect to socio-economic status and race/ethnicity. METHODS: A retrospective cohort study was carried out using individual and census-based neighbourhood data. Consecutive patients in urban tertiary care centres with biopsy-proven PLN were studied. The main outcome was time to doubling of serum creatinine. RESULTS: Among 128 patients with PLN, the percentage of patients who did not double their serum creatinine at 5 years was 67.0% (+/-4.8%) and at 10 years was 58.9% (+/-5.7%). In bivariate analyses, residence in a poor neighbourhood was positively associated with progression (P = 0.03), as was African-American and Hispanic race/ethnicity (P = 0.01). Residence in a poor neighbourhood remained associated with progression of disease after adjustment for age, sex, creatinine, hypertension, cyclophosphamide treatment and race/ethnicity [relative risk (RR) 3.5, 95% confidence interval (CI) 1.2-11, P = 0.03]. After adjustment for poverty and insurance, the RR for African-American race/ethnicity was reduced from 3.5 to 2.7 and was not statistically associated with progression of disease in the full model (P = 0.10). A similar reduction in RR from 5.5 to 3.6 was seen for Hispanic race/ethnicity, but this retained statistical significance (P = 0.03). CONCLUSIONS: Poverty is an important risk factor for progression of PLN, independent of race/ethnicity. Hispanics have an elevated risk similar to or greater than African-Americans. Given these findings, some of the poorer prognosis of African-American patients with PLN may result from socio-economic rather than biological or genetic factors.

Adolescent↗
PubMed2003

Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy.

Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is proposed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies.

Animals↗
PubMed2002

Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) occurs by germline mutation in PKD1 or PKD2. Evidence of homozygous inactivation of either gene in human cyst lining cells as well as in mouse knockout models strongly supports a two-hit mechanism for cyst formation. Discovery of trans-heterozygous mutations in PKD1 and PKD2 in a minority of human renal cysts has led to the proposal that such mutations also can play a role in cyst formation. In the current study, we investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1(+/-), Pkd2 (+/-) and Pkd1(+/-) : Pkd2 (+/-) mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the two-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 (+/-) mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1(+/-) : Pkd2 (+/-) mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. The data suggest a modifier role for the 'trans' polycystin gene in cystic kidney disease, and support a contribution from threshold effects to cyst formation and growth.

Animals↗