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Biomedical subjects

Laura Barisoni

Publications and source records attributed to Laura Barisoni.

7 recordsLinked to original sources
PubMed2003

Podocyte biology and the emerging understanding of podocyte diseases.

The understanding of the unique molecular apparatus of the podocyte has increased dramatically in recent years. This new knowledge has improved the diagnosis and classification of the diseases that have been termed podocytopathies. Podocyte injury frequently leads to reorganization of the slit diaphragm and reorganization of the foot process structure. Four major causes of foot process effacement can be identified, with some due to genetic mutations and others due to acquired conditions: (1) impaired formation of the slit diaphragm complex; (2) abnormalities of the glomerular basement membrane or the adhesion of podocytes to the glomerular basement membrane; (3) abnormalities of the actin cytoskeleton and associated proteins, and (4) alterations in the apical membrane domain of the podocyte. The major podocytopathies can also be organized into four categories, including those with a normal glomerular histology, diffuse mesangial sclerosis, focal segmental glomerulosclerosis, and collapsing glomerulopathy.

Glomerulonephritis↗
PubMed2003

Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations.

HIV infection is associated with several renal syndromes, including acute renal failure. Chronic renal failure directly linked to HIV infection includes thrombotic microangiopathic renal diseases, immune-mediated glomerulonephritides, and HIV-associated nephropathy. A renal biopsy may be necessary for diagnosis. The development of HIV-associated nephropathy has been definitively linked to renal cellular infection, but the disease affects only a minority of patients, typically men of African descent. Therefore, factors determining disease expression in infected patients must now be emphasized. The pathogenic mechanisms involved in HIV-associated renal disease remain obscure. Genetic factors, as well as renal cellular responses, mediated by HIV proteins (including an immune-activated microenvironment) capable of presenting antigen in susceptible hosts probably explain most cases. HIV-associated nephropathy has a characteristic pathologic phenotype, including glomerular, tubular, and interstitial changes, and ultrastructural findings. Infection of the glomerular epithelial cell, or podocyte, and consequent structural and biochemical changes may be pivotal in pathogenesis. The HIV-1 transgenic mouse is an important model for understanding disease pathogenesis, particularly the role of HIV proteins in mediating renal tissue injury. Rigorously controlled randomized trials have not evaluated treatment, but corticosteroids and angiotensin-converting enzyme inhibitors have been used. Highly active antiretroviral therapy seems to have decreased the incidence of end-stage renal disease related to HIV infection and, in case reports, to have improved renal functional and pathologic outcomes of HIV-associated nephropathy. Outcomes in patients undergoing hemodialysis and peritoneal dialysis have improved, and current research focuses on renal transplantation for treatment of HIV-infected patients.

Animals↗
PubMed2003

Update in podocyte biology: putting one's best foot forward.

PURPOSE OF REVIEW: The rapidly developing field of podocyte cell biology is reviewed, focusing on papers published in the last 12 months. RECENT FINDINGS: Four areas of particular progress can be discerned. First, podocytes proliferate during early metanephric development, are quiescent after the capillary loop stage, and re-enter the cell cycle only in the disease group termed collapsing glomerulopathy. We have learned that control of the podocyte cell cycle involves both expression of cell-cycle regulating proteins and the process of cytokinesis. Second, the podocyte slit diaphragm is the final component of the filtration barrier. The structure and maintenance of the slit diaphragm has been a major focus of research activity, and a multiplicity of relevant molecular interactions have been defined. Significant advances have been made in understanding the complex and interacting role of nephrin and podocin mutations in the genesis of clinical glomerular disease. Third, several proteins essential to controlling discrete podocyte transcriptional programs have been defined. Finally, conditionally-immortalized podocyte cell lines, derived from mouse and human tissue, have proven their worth as models to advance investigations of podocyte biology. SUMMARY: Podocyte injury occurs as a consequence of genetic mutation, immunological injury, viral infection, or abnormal hemodynamic forces within the glomerulus. As we understand more about the podocyte proteome and cell biology, we gain an increasingly detailed molecular understanding of podocyte structure and function. In this drama we have many molecular players and increasing stretches of molecular dialogue, but the script remains largely to be deciphered. Nevertheless, we do understand the consequences that arise when the podocyte cannot put its best foot (processes) forward.

Animals↗
PubMed2003

Anti-mouse mesangial cell serum induces acute glomerulonephropathy in mice.

In order to develop a model in mouse similar to anti- Thy-1 nephritis in the rat, we prepared sheep antiserum against SV40-transformed mouse mesangial (MES 13) cells. In vivo, the anti-mouse mesangial cell serum-treated mice showed severe azotemia that peaked at day 6 and proteinuria that peaked at day 8, in a dose-dependent fashion. Light microscopy and electron microscopy showed duplication of glomerular basement membranes, mesangiolysis, subendothelial and mesangial electron-dense deposits, and foot process effacement. Intraglomerular tuft cell number was significantly reduced at day 4 and there were increased numbers of apoptotic cells at days 2 and 4. SCID mice and mice lacking C3 manifested similar responses to anti-mouse mesangial cell serum, suggesting that T cells, B cells and complement are not required for glomerular injury in this model. In vitro, anti-mouse mesangial cell serum treated mesangial cells showed greater release of lactate dehydrogenase, decreased cell survival, and increased apoptotic cell death. Anti-mouse mesangial cell serum induces glomerulopathy characterized by mesangiolysis and mesangial cell apoptosis, and followed by cellular proliferation.

3T3 Cells↗
PubMed2002

Modulation of podocyte phenotype in collapsing glomerulopathies.

Podocytes are well-differentiated postmitotic cells whose function is largely based on their complex cytoskeletal architecture. In diseases with proteinuria, podocytes undergo morphologic changes. Podocytes react to an injurious stimulus by a reorganization of their foot process architecture that is independent of the primary injury and the cause of the proteinuria. Collapsing glomerulopathies, including the idiopathic and secondary forms due to HIV infection, have been previously considered a part of the focal sclerosing glomerulosclerosis (FSGS) spectrum. However, in contrast to FSGS, both forms of collapsing glomerulopathy are characterized by segmental and global collapse of the glomerular basement membrane (GBM) and by characteristic ultrastructural alterations in podocytes. These alterations include loss of the actin-based cytoskeleton, a dysregulated/dedifferentiated phenotype, cellular hypertrophy, and cell proliferation. These observations raise the following questions: 1) What mechanism causes glomerular collapse and do podocytes have a role? We recently proposed that in collapsing glomerulopathies the composition of the GBM is altered and contains more immature forms of collagen IV. These observations suggest that dedifferentiated/dysregulated podocytes may participate in remodeling the GBM composition, producing fetal collagen isoforms. 2) What is the pathomechanism underlying podocyte dysregulation? Although it is still unclear which etiologic factors are responsible for the idiopathic forms of collapsing glomerulopathy, in situ hybridization studies in a transgenic mouse model of HIV-associated collapsing glomerulopathy and on renal biopsies of patients with HIV-associated collapsing glomerulopathy demonstrated the presence of the HIV-1 RNA in podocytes and tubular epithelial cells. These findings suggest a direct link between viral gene expression and the dysregulation of the podocyte phenotype. 3) Another open question is how podocytes become infected in HIV-associated collapsing glomerulopathy. HIV-1 typically uses CD4 and a co-receptor such as CCR5 or CXCR4 to enter cells. So far, there is no demonstration of the expression of these receptors in podocytes. These negative findings, however, do not exclude the possibility that in the kidney another, CD4 independent, co-receptor may be used for viral cell entry. Finally, is it important to mention that collapsing glomerulopathies have a high prevalence in black patients, suggesting a link between racial background and the virus-related podocyte injury.

Cell Size↗
PubMed2002

Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome.

This study addresses the biological function of the p53-effector genes Gadd45a and p21 in the immune system. We find that Gadd45a is a negative regulator of T cell proliferation because, compared to wild-type cells, Gadd45a(-/-) T cells have a lower threshold of activation and proliferate to a greater extent following primary T cell receptor stimulation. Gadd45a(-/-) mice develop an autoimmune disease, similar to human systemic lupus erythematosus (SLE), characterized by high titers of anti-dsDNA, anti-ssDNA, and anti-histone autoantibodies, severe hematological disorders, autoimmune glomerulonephritis, and premature death. Here we show that the lack of both Gadd45a and p21 dramatically accelerates the development of autoimmunity observed in each individual single-gene disruption mutant, demonstrating that these genes play nonredundant roles in the immune response.

Animals↗