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Paul E. Klotman - One of the best experts on this subject based on the ideXlab platform.
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Recent progress in HIV-Associated Nephropathy.
Annual review of medicine, 2011Co-Authors: Christina M. Wyatt, Kristin Meliambro, Paul E. KlotmanAbstract:Abstract The classic kidney disease of HIV infection, HIV-Associated Nephropathy (HIVAN), is an aggressive form of collapsing focal segmental glomerulosclerosis with accompanying tubular and interstitial lesions. HIVAN was first described among African-Americans and Haitian immigrants with advanced HIV disease, an early suggestion of a strong genetic association. This genetic susceptibility was recently linked to polymorphisms on chromosome 22 in individuals of African descent. The association with advanced HIV infection and evidence from HIV-transgenic mice suggested the possibility that HIV directly infects the kidney and that specific HIV gene expression induces host cellular pathways that are responsible for HIVAN pathogenesis. Although combination antiretroviral therapy has substantially reduced the impact of HIVAN in the United States, continued growth of the HIV epidemic in susceptible African populations may have important public health implications. This article reviews recent progress in the pathogenesis and treatment of HIVAN and describes the changing epidemiology of HIV-related kidney disease.
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HIV- Associated Nephropathy: Pathogenesis
Current opinion in nephrology and hypertension, 2011Co-Authors: Raj Kiran Medapalli, Paul E. KlotmanAbstract:Purpose of review HIV-Associated Nephropathy (HIVAN) is characterized histologically by a collapsing form of focal segmental glomerulosclerosis (FSGS), microcystic tubular dilation, interstitial inflammation and fibrosis. In this review, we provide a summary of the current state of knowledge about the mechanisms involved in the pathogenesis of HIVAN. Recent findings Two variants in the ApoL1 gene have been identified as the susceptibility alleles that account for a majority of the increased risk of FSGS and nondiabetic end-stage renal disease in blacks. HIVAN1 and HIVAN2 are the other host susceptibility genes that have been identified in animal models for HIVAN. HIV infects renal tubular epithelial cells likely through direct cell-cell transmission. Both in-vivo and in-vitro evidence suggests that Nef and Vpr are the key viral genes mediating HIVAN. Nef induces podocyte dysfunction, whereas Vpr induces renal tubular epithelial cell apoptosis. Summary HIVAN results from direct infection by HIV-1 and expression of viral genes, especially Nef and Vpr, in renal epithelial cells in a genetically susceptible host. The infected renal epithelium acts as a separate viral compartment from the blood and facilitates evolution of strains distant from blood. Dysregulation of several host cellular pathways, including those involved in cell cycle and apoptosis, ultimately results in the unique histopathological syndrome of HIVAN.
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The pathogenesis of HIV-Associated Nephropathy.
Advances in chronic kidney disease, 2010Co-Authors: Lewis Kaufman, Susan E. Collins, Paul E. KlotmanAbstract:HIV-Associated Nephropathy (HIVAN) is one of the leading causes of ESRD in HIV-1-seropositive patients. Patients typically present with heavy proteinuria and chronic renal failure with pathologic findings of collapsing focal segmental glomerulosclerosis (FSGS). The disease is caused by direct infection of renal epithelial cells by HIV-1 in a genetically susceptible host. The genetic factors responsible for the susceptibility to HIVAN among blacks include a noncoding variant in the podocyte-expressed gene nonmuscle myosin, heavy chain 9 (MYH9) as well as other genes yet to be identified. Podocyte and tubular dysfunction results from the expression of viral genes, in particular nef and vpr, and the subsequent dysregulation of numerous host factors, including critical signaling pathways, inflammatory mediators, and others. The identification of these factors has the potential to provide novel therapeutic targets to prevent and treat this important disease.
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Transgenic and Infectious Animal Models of HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2009Co-Authors: Paul E. Rosenstiel, Vivette D. D'agati, Ali G. Gharavi, Paul E. KlotmanAbstract:HIV-Associated Nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Transgenic and infectious models of HIVAN faithfully recapitulate the human disease and are important tools in advancing our understanding of disease pathogenesis, genetic susceptibility, and therapeutic intervention beyond the inhibition of viral replication. This review discusses the available transgenic murine models and infectious models of HIVAN in mice, rats, nonhuman primates, and felines. Particular emphasis is given to cell type-specific HIV expression as well as partial HIV genome expression used to map HIV-1 Nef and Vpr as pathologic determinants.
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Chapter 47 – HIV-Associated Nephropathy
Genetic Diseases of the Kidney, 2009Co-Authors: Christina M. Wyatt, Paul E. KlotmanAbstract:Publisher Summary This chapter provides information on histology, epidemiology, pathogenesis, genetic factors, and treatment Associated with HIV-Associated Nephropathy, or HIVAN. In classic HIVAN, the kidneys are enlarged or normal in size on gross examination, consistent with the histologic findings of glomerular and tubular epithelial proliferation. The glomerular lesion of HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS), characterized by podocyte proliferation and dedifferentiation. Renal tissue from patients with idiopathic or HIV-Associated collapsing FSGS demonstrates loss of podocyte maturity markers, including synaptopodin, podocalyxin, and the Wilms’ tumor antigen WT-1. The predilection of HIVAN for seropositive patients of African descent suggests that host genetic factors play an important role in the pathogenesis of HIVAN. Expression of HIV-1 mRNA in tubular epithelial cells can be detected throughout the renal tubule in biopsies from patients with HIVAN. The pattern of viral mRNA expression is similar to the development of tubular microcysts, consistent with a pathogenic role for viral infection. There are currently no randomized clinical trial data to guide the treatment of HIVAN. Limited observational data have suggested a potential role for corticosteroids and inhibitors of the renin-angiotensin-aldosterone system. The rationale for use of corticosteroids in HIVAN is extrapolated from limited data in other renal diseases with overlapping clinical or histologic features, including hepatitis C virus-related membranoproliferative glomerulonephritis and idiopathic FSGS. In addition, corticosteroids have been hypothesized to ameliorate the inflammatory interstitial component of HIVAN. The established benefit of ACE inhibitors in other proteinuric renal diseases formed the basis for their initial use in HIVAN.
Christina M. Wyatt - One of the best experts on this subject based on the ideXlab platform.
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APOL1 variants in HIV-Associated Nephropathy: just one piece of the puzzle.
Kidney international, 2012Co-Authors: Thomas Hays, Christina M. WyattAbstract:Considerable attention has been focused on how the APOL1 / MYH9 locus determines susceptibility to focal segmental glomerulosclerosis, including HIV-Associated Nephropathy (HIVAN). Atta and colleagues found that homozygosity for APOL1 risk alleles was Associated with many, but not all, HIVAN cases, and that APOL1 variation failed to predict characteristics of disease. Their work gives important impetus to identify other genetic and environmental factors that may provide a ‘second hit' linking HIV infection to HIVAN.
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Recent progress in HIV-Associated Nephropathy.
Annual review of medicine, 2011Co-Authors: Christina M. Wyatt, Kristin Meliambro, Paul E. KlotmanAbstract:Abstract The classic kidney disease of HIV infection, HIV-Associated Nephropathy (HIVAN), is an aggressive form of collapsing focal segmental glomerulosclerosis with accompanying tubular and interstitial lesions. HIVAN was first described among African-Americans and Haitian immigrants with advanced HIV disease, an early suggestion of a strong genetic association. This genetic susceptibility was recently linked to polymorphisms on chromosome 22 in individuals of African descent. The association with advanced HIV infection and evidence from HIV-transgenic mice suggested the possibility that HIV directly infects the kidney and that specific HIV gene expression induces host cellular pathways that are responsible for HIVAN pathogenesis. Although combination antiretroviral therapy has substantially reduced the impact of HIVAN in the United States, continued growth of the HIV epidemic in susceptible African populations may have important public health implications. This article reviews recent progress in the pathogenesis and treatment of HIVAN and describes the changing epidemiology of HIV-related kidney disease.
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Urinary NGAL Marks Cystic Disease in HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2009Co-Authors: Neal Paragas, Christina M. Wyatt, Thomas L. Nickolas, Catherine S. Forster, Meghan E. Sise, Susan Morgello, Bernd Jagla, Charles Buchen, Peter Stella, Simone Sanna-cherchiAbstract:Nephrosis and a rapid decline in kidney function characterize HIV-Associated Nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glomerulosclerosis with prominent tubular damage. We explored the expression of neutrophil gelatinase-Associated lipocalin (NGAL), a marker of tubular injury, to determine whether this protein has the potential to aid in the noninvasive diagnosis of HIVAN. We found that expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative patients with other forms of chronic kidney disease. In the HIV-transgenic mouse model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of the nephron. In contrast, urinary NGAL did not correlate with proteinuria in human or in mouse models. These data show that marked upregulation of NGAL accompanies HIVAN and support further study of uNGAL levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage.
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Chapter 47 – HIV-Associated Nephropathy
Genetic Diseases of the Kidney, 2009Co-Authors: Christina M. Wyatt, Paul E. KlotmanAbstract:Publisher Summary This chapter provides information on histology, epidemiology, pathogenesis, genetic factors, and treatment Associated with HIV-Associated Nephropathy, or HIVAN. In classic HIVAN, the kidneys are enlarged or normal in size on gross examination, consistent with the histologic findings of glomerular and tubular epithelial proliferation. The glomerular lesion of HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS), characterized by podocyte proliferation and dedifferentiation. Renal tissue from patients with idiopathic or HIV-Associated collapsing FSGS demonstrates loss of podocyte maturity markers, including synaptopodin, podocalyxin, and the Wilms’ tumor antigen WT-1. The predilection of HIVAN for seropositive patients of African descent suggests that host genetic factors play an important role in the pathogenesis of HIVAN. Expression of HIV-1 mRNA in tubular epithelial cells can be detected throughout the renal tubule in biopsies from patients with HIVAN. The pattern of viral mRNA expression is similar to the development of tubular microcysts, consistent with a pathogenic role for viral infection. There are currently no randomized clinical trial data to guide the treatment of HIVAN. Limited observational data have suggested a potential role for corticosteroids and inhibitors of the renin-angiotensin-aldosterone system. The rationale for use of corticosteroids in HIVAN is extrapolated from limited data in other renal diseases with overlapping clinical or histologic features, including hepatitis C virus-related membranoproliferative glomerulonephritis and idiopathic FSGS. In addition, corticosteroids have been hypothesized to ameliorate the inflammatory interstitial component of HIVAN. The established benefit of ACE inhibitors in other proteinuric renal diseases formed the basis for their initial use in HIVAN.
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HIV-Associated Nephropathy : Clinical Presentation, Pathology, and Epidemiology in the Era of Antiretroviral Therapy
Seminars in nephrology, 2008Co-Authors: Christina M. Wyatt, Paul E. Klotman, Vivette D. D'agatiAbstract:The classic kidney disease of human immunodeficiency virus (HIV) infection, HIV-Associated Nephropathy, is characterized by progressive acute renal failure, often accompanied by proteinuria and ultrasound findings of enlarged, echogenic kidneys. Definitive diagnosis requires kidney biopsy, which shows collapsing focal segmental glomerulosclerosis with Associated microcystic tubular dilatation and interstitial inflammation. Podocyte proliferation is a hallmark of HIV-Associated Nephropathy, although this classic pathology is observed less frequently in antiretroviral-treated patients. The pathogenesis of HIV-Associated Nephropathy involves direct HIV infection of renal epithelial cells, and the widespread introduction of combination antiretroviral therapy has had a significant impact on the natural history and epidemiology of this unique disease. These observations have established antiretroviral therapy as the cornerstone of treatment for HIV-Associated Nephropathy in the absence of prospective clinical trials. Adjunctive therapy for HIV-Associated Nephropathy includes angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, as well as corticosteroids in selected patients with significant interstitial inflammation or rapid progression.
Michael W. Ross - One of the best experts on this subject based on the ideXlab platform.
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Molecular Mechanisms of Injury in HIV-Associated Nephropathy.
Frontiers in medicine, 2018Co-Authors: Samuel J. Rednor, Michael W. RossAbstract:HIV-Associated Nephropathy (HIVAN) is an important cause of secondary focal glomerulosclerosis that occurs primarily in persons of African ancestry with advanced HIV disease. Although HIVAN is characterized by severe proteinuria and rapid progression to end stage renal disease without treatment, the phenotype is markedly attenuated by treatment with antiretroviral medications. HIV infection of glomerular and tubular epithelial cells and subsequent viral gene expression is a key contributor to HIVAN pathogenesis and the kidney can serve as reservoir for HIV strains that differ those in blood. HIV gene expression in renal epithelial cells leads to dysregulation of cellular pathways including cell cycle, inflammation, cell death, and cytoskeletal homeostasis. Polymorphisms in the APOL1 gene explain the marked predilection of HIVAN to occur in persons of African descent and HIVAN. Since HIVAN has the strongest association with APOL1 genotype of any of the APOL1-Associated nephropathies, studies to determine the mechanisms by which HIV and APOL1 risk variants together promote kidney injury hold great promise to improve our understanding of the pathogenesis of APOL1-mediated kidney diseases.
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Dual tropism of HIV-1 envelopes derived from renal tubular epithelial cells of patients with HIV-Associated Nephropathy.
AIDS (London England), 2006Co-Authors: Bouchra Zerhouni-layachi, Paul E. Klotman, Michael W. Ross, Mohammad Husain, Daniele Marras, Masaaki Sunamoto, Xinyan Liu, Mary E. KlotmanAbstract:The phenotype of HIV-1 gp120 envelope derived from renal epithelium and peripheral blood mononuclear cells (PBMC) of patients with HIV-Associated Nephropathy was investigated in vitro. Chimeric viruses were derived from kidney or blood and used to infect primary CD4+T cells, cell lines expressing single co-receptors and a renal epithelial cell line HPT-1. HIV-1 variants derived from renal epithelium were dual tropic whereas simultaneously derived viruses from PBMC were R5-tropic. Utilization of alternative co-receptors CCR3, BONZO and BOB, also differed.
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NF-κB regulates Fas-mediated apoptosis in HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Michael W. Ross, Vivette D. D'agati, Scott Martinka, Leslie A. BruggemanAbstract:Renal parenchymal injury in HIV-Associated Nephropathy (HIVAN) is characterized by epithelial proliferation, dedifferentiation, and apoptosis along the entire length of the nephron. Although apoptotic cell death in HIVAN has been well documented, the mechanism for HIV-induced apoptosis is poorly understood. We investigated here whether the epithelial apoptosis in HIVAN is mediate by NF-κB-activated Fas ligand expression. In human HIVAN and HIV-1 transgenic mouse kidney specimens, the expression of Fas receptor and ligand proteins were markedly up-regulated on epithelium in diseased glomerular and tubulointerstitial compartments when compared to normal. Podocyte cell lines derived from HIV-1 transgenic mice showed a similar up-regulation of Fas receptor expression and de novo expression of Fas ligand by semi-quantitative rt/PCR and Western blotting. In cultured podocytes, crosslinking of the Fas receptor to mimic ligand binding induced caspase 8 activity and apoptosis in both normal and HIVAN podocytes. Since we have demonstrated constitutive NF-κB activity in HIVAN epithelia, we sought evidence for transcriptional control of the Fas ligand expression by NF-κB. Using cultured podocytes, expression of a FasL reporter promoter plasmid was higher in HIVAN podocytes indicating increase transcriptional activity. In addition, chromatin immunoprecipitation assays were performed to demonstrate p65 (RelA) containing complexes bound the Fas ligand promoter, and that suppression of activated NF-κB with a peptide inhibitor could reduce the expression of Fas ligand mRNA in HIVAN podocytes. These results suggest that NF-κB may regulate Fas-mediated apoptosis in HIVAN by controlling the expression of Fas ligand in renal epithelium.
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HIV-Associated Nephropathy: a brief review.
The Mount Sinai journal of medicine New York, 2005Co-Authors: Michael W. RossAbstract:HIV-Associated Nephropathy (HIVAN) is an important cause of renal failure in HIV-1 seropositive patients. The disease is characterized by collapsing focal segmental glomerulosclerosis with marked podocyte proliferation, microcystic dilatation of the tubules and interstitial nephritis. Patients generally present with advanced HIV-1 infection, renal insufficiency and marked proteinuria. No serologic markers exist to diagnose HIVAN, and given the broad differential diagnosis for renal failure in these patients, renal biopsy should be performed. Viral infection of renal cells plays a central role in the pathogenesis of HIVAN. There is now compelling evidence that highly active antiretroviral therapy (HAART) is effective in preventing end-stage renal disease in patients affected with HIVAN. The efficacy of angiotensin-converting enzyme (ACE) inhibitors and prednisone has also been evaluated, but larger prospective studies are needed.
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Sidekick-1 Is Upregulated in Glomeruli in HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2004Co-Authors: Lewis Kaufman, Michael W. Ross, Kayo Hayashi, Michael D. Ross, Paul E. KlotmanAbstract:Infection of podocytes by HIV-1 induces unique changes in phenotype, which contribute to the pathogenesis of glomerular disease in HIV-Associated Nephropathy (HIVAN). The host genetic pathways altered by HIV-1 infection that are responsible for these phenotypic changes are largely unknown. For identifying such pathways, representational difference analysis was performed comparing cDNA from HIV-1 transgenic podocytes with nontransgenic controls. In this way, a gene named sidekick-1 (sdk-1) was cloned, a transmembrane protein of the Ig superfamily that is highly upregulated in HIV-1 transgenic podocytes. Sdk-1 and its ortholog, sidekick-2 (sdk-2), were recently shown to guide axonal terminals to specific synapses in developing neurons. Their presence and role in other organs, including the kidney, has not been described. The current study demonstrates developmental expression of both sdk-1 and sdk-2 and a tight spatial and temporal regulation of these genes in kidney. During nephrogenesis, sidekick expression was observed first in ureteric bud and ureteric bud-derived tissues in a pattern similar to other genes known to play important roles in branching morphogenesis. In adult murine renal tissue, sidekick proteins were seen in glomeruli at low levels, and expression of sdk-1 was greatly upregulated in diseased HIV-1 transgenic mouse kidneys. In a human HIVAN kidney biopsy, sidekick expression was increased in glomeruli in a pattern consistent with the mouse model. It is proposed that the dysregulation of sdk-1 protein may play an important role in HIVAN pathogenesis.
Vivette D. D'agati - One of the best experts on this subject based on the ideXlab platform.
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Urinary NGAL is a useful clinical biomarker of HIV-Associated Nephropathy
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2011Co-Authors: David Sola-del Valle, Vivette D. D'agati, Jen-tse Cheng, Neal Paragas, Meghan E. Sise, Sumit Mohan, Jonathan M. BaraschAbstract:Background. Urinary neutrophil gelatinase-Associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-Associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-Associated Nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end-stage renal disease (ESRD). Methods. Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive. Results. Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 ± 338 versus 94 ± 101 μg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 μg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88. Conclusion. In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts.
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Transgenic and Infectious Animal Models of HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2009Co-Authors: Paul E. Rosenstiel, Vivette D. D'agati, Ali G. Gharavi, Paul E. KlotmanAbstract:HIV-Associated Nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Transgenic and infectious models of HIVAN faithfully recapitulate the human disease and are important tools in advancing our understanding of disease pathogenesis, genetic susceptibility, and therapeutic intervention beyond the inhibition of viral replication. This review discusses the available transgenic murine models and infectious models of HIVAN in mice, rats, nonhuman primates, and felines. Particular emphasis is given to cell type-specific HIV expression as well as partial HIV genome expression used to map HIV-1 Nef and Vpr as pathologic determinants.
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HIV-Associated Nephropathy : Clinical Presentation, Pathology, and Epidemiology in the Era of Antiretroviral Therapy
Seminars in nephrology, 2008Co-Authors: Christina M. Wyatt, Paul E. Klotman, Vivette D. D'agatiAbstract:The classic kidney disease of human immunodeficiency virus (HIV) infection, HIV-Associated Nephropathy, is characterized by progressive acute renal failure, often accompanied by proteinuria and ultrasound findings of enlarged, echogenic kidneys. Definitive diagnosis requires kidney biopsy, which shows collapsing focal segmental glomerulosclerosis with Associated microcystic tubular dilatation and interstitial inflammation. Podocyte proliferation is a hallmark of HIV-Associated Nephropathy, although this classic pathology is observed less frequently in antiretroviral-treated patients. The pathogenesis of HIV-Associated Nephropathy involves direct HIV infection of renal epithelial cells, and the widespread introduction of combination antiretroviral therapy has had a significant impact on the natural history and epidemiology of this unique disease. These observations have established antiretroviral therapy as the cornerstone of treatment for HIV-Associated Nephropathy in the absence of prospective clinical trials. Adjunctive therapy for HIV-Associated Nephropathy includes angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, as well as corticosteroids in selected patients with significant interstitial inflammation or rapid progression.
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NF-κB regulates Fas-mediated apoptosis in HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Michael W. Ross, Vivette D. D'agati, Scott Martinka, Leslie A. BruggemanAbstract:Renal parenchymal injury in HIV-Associated Nephropathy (HIVAN) is characterized by epithelial proliferation, dedifferentiation, and apoptosis along the entire length of the nephron. Although apoptotic cell death in HIVAN has been well documented, the mechanism for HIV-induced apoptosis is poorly understood. We investigated here whether the epithelial apoptosis in HIVAN is mediate by NF-κB-activated Fas ligand expression. In human HIVAN and HIV-1 transgenic mouse kidney specimens, the expression of Fas receptor and ligand proteins were markedly up-regulated on epithelium in diseased glomerular and tubulointerstitial compartments when compared to normal. Podocyte cell lines derived from HIV-1 transgenic mice showed a similar up-regulation of Fas receptor expression and de novo expression of Fas ligand by semi-quantitative rt/PCR and Western blotting. In cultured podocytes, crosslinking of the Fas receptor to mimic ligand binding induced caspase 8 activity and apoptosis in both normal and HIVAN podocytes. Since we have demonstrated constitutive NF-κB activity in HIVAN epithelia, we sought evidence for transcriptional control of the Fas ligand expression by NF-κB. Using cultured podocytes, expression of a FasL reporter promoter plasmid was higher in HIVAN podocytes indicating increase transcriptional activity. In addition, chromatin immunoprecipitation assays were performed to demonstrate p65 (RelA) containing complexes bound the Fas ligand promoter, and that suppression of activated NF-κB with a peptide inhibitor could reduce the expression of Fas ligand mRNA in HIVAN podocytes. These results suggest that NF-κB may regulate Fas-mediated apoptosis in HIVAN by controlling the expression of Fas ligand in renal epithelium.
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The Dysregulated Podocyte Phenotype A Novel Concept in the Pathogenesis of Collapsing Idiopathic Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 1998Co-Authors: Laura Barisoni, Wilhelm Kriz, Peter Mundel, Vivette D. D'agatiAbstract:Podocytes are highly differentiated, postmitotic cells, whose function is largely based on their complex cytoarchitecture. The differentiation of podocytes coincides with progressive expression of maturity markers, including WT-1, CALLA, C3b receptor, GLEPP-1, podocalyxin, and synaptopodin. In collapsing forms of focal segmental glomerulosclerosis (FSGS), including idiopathic FSGS and HIV-Associated Nephropathy, podocytes undergo characteristic, irreversible ultrastructural changes. This study analyzes the expression pattern of the above differentiation markers and of the proliferation marker Ki-67 in collapsing idiopathic FSGS and HIV-Associated Nephropathy compared with minimal change disease, membranous glomerulopathy, as well as normal adult and fetal human kidney. In minimal change disease and membranous glomerulopathy, all mature podocyte markers were retained at normal levels despite severe proteinuria and foot process fusion; no cell proliferation was observed. In contrast, in collapsing idiopathic FSGS and HIV-Associated Nephropathy, there was disappearance of all markers from all collapsed glomeruli and of synaptopodin from 16% of noncollapsed glomeruli. This phenotypic dysregulation of podocytes was Associated with cell proliferation in both diseases. It is concluded that the loss of specific podocyte markers defines a novel dysregulated podocyte phenotype and suggests a common pathomechanism in collapsing FSGS, whether idiopathic or HIV-Associated.
Leslie A. Bruggeman - One of the best experts on this subject based on the ideXlab platform.
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APOL1-G0 protects podocytes in a mouse model of HIV-Associated Nephropathy.
PloS one, 2019Co-Authors: Leslie A. Bruggeman, Laura Barisoni, Liping Luo, Sethu M. Madhavan, Paul E. Drawz, David B. Thomas, John F. O'toole, John R. SedorAbstract:African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-Associated Nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Transgene expression, survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups. APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This was absent with APOL1-G2 expression, suggesting APOL1-G2 may have lost this protective function.
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APOL1-G0 protects podocytes in a mouse model of HIV-Associated Nephropathy
2019Co-Authors: Leslie A. Bruggeman, Laura Barisoni, Liping Luo, Sethu M. Madhavan, Paul E. Drawz, David B. Thomas, John F. O'toole, John R. SedorAbstract:ABSTRACT Background African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-Associated Nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. Methods The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Results Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups. Conclusions APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This function appears to be absent with APOL1-G2 expression, suggesting APOL1-G2 is a loss-of-function variant.
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Persistent NF-κB activation in renal epithelial cells in a mouse model of HIV-Associated Nephropathy
American journal of physiology. Renal physiology, 2005Co-Authors: Scott Martinka, Leslie A. BruggemanAbstract:Human immunodeficiency virus (HIV)-Associated Nephropathy (HIVAN) is caused, in part, by direct infection of kidney epithelial cells by HIV-1. In the spectrum of pathogenic host-virus interactions,...
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NF-κB regulates Fas-mediated apoptosis in HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Michael W. Ross, Vivette D. D'agati, Scott Martinka, Leslie A. BruggemanAbstract:Renal parenchymal injury in HIV-Associated Nephropathy (HIVAN) is characterized by epithelial proliferation, dedifferentiation, and apoptosis along the entire length of the nephron. Although apoptotic cell death in HIVAN has been well documented, the mechanism for HIV-induced apoptosis is poorly understood. We investigated here whether the epithelial apoptosis in HIVAN is mediate by NF-κB-activated Fas ligand expression. In human HIVAN and HIV-1 transgenic mouse kidney specimens, the expression of Fas receptor and ligand proteins were markedly up-regulated on epithelium in diseased glomerular and tubulointerstitial compartments when compared to normal. Podocyte cell lines derived from HIV-1 transgenic mice showed a similar up-regulation of Fas receptor expression and de novo expression of Fas ligand by semi-quantitative rt/PCR and Western blotting. In cultured podocytes, crosslinking of the Fas receptor to mimic ligand binding induced caspase 8 activity and apoptosis in both normal and HIVAN podocytes. Since we have demonstrated constitutive NF-κB activity in HIVAN epithelia, we sought evidence for transcriptional control of the Fas ligand expression by NF-κB. Using cultured podocytes, expression of a FasL reporter promoter plasmid was higher in HIVAN podocytes indicating increase transcriptional activity. In addition, chromatin immunoprecipitation assays were performed to demonstrate p65 (RelA) containing complexes bound the Fas ligand promoter, and that suppression of activated NF-κB with a peptide inhibitor could reduce the expression of Fas ligand mRNA in HIVAN podocytes. These results suggest that NF-κB may regulate Fas-mediated apoptosis in HIVAN by controlling the expression of Fas ligand in renal epithelium.
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Microcyst Formation and HIV-1 Gene Expression Occur in Multiple Nephron Segments in HIV-Associated Nephropathy
Journal of the American Society of Nephrology : JASN, 2001Co-Authors: Michael W. Ross, Leslie A. Bruggeman, Patricia D. Wilson, Paul E. KlotmanAbstract:Tubular microcyst formation is a prominent histopathologic feature of HIV-Associated Nephropathy (HIVAN), but its pathogenesis is unknown. HIV-1 has recently been shown to infect renal tubular epithelial cells in patients with HIVAN. In addition, HIV-1 gene expression in renal epithelial cells has been shown to cause a renal disease that is identical to HIVAN in HIV-1 transgenic mice. In these studies, immunohistochemistry for tubular segment-specific markers and mRNA in situ hybridization for HIV-1 was used to determine which tubular segments develop microcysts and which segments express HIV-1 in the kidneys of transgenic mice and patients with HIVAN. It was found that microcysts involve multiple nephron segments in both patients with HIVAN and HIV-1 transgenic mice. Furthermore, HIV-1 infection in HIVAN and HIV-1 transgene expression also occurs in multiple segments of the nephron. These data support a direct role for HIV-1 infection of renal epithelial cells in the pathogenesis of microcyst formation in patients with HIVAN.