Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic.? ? In order to define the molecular mechanisms responsible for HIV-associated collapsing glomerulopathy, we have established mice in which transgene expression can be regulated in the glomerular podocyte using an tetracycline-regulated system. We have used this system to express the HIV-1 accessory protein Vpr in the podocyte. These mice develop proteinuria beginning 4 weeks after treatment with tetracycline. Collapsing glomerulopathy appears at 8 weeks, progressing to global glomerulosclerosis and end-stage kidney disease. Podocyte phenotype is abnormal, with reduced expression of the differentiation marker synaptopodin and de novo expression of the injury marker desmin. Increased cell proliferation is present in the glomerular tuft, parietal epithelum, and tubular epithelium. These results demonstrate that Vpr is sufficient to induce HIV-associated collapsing glomerulopathy in transgenic mice. ? ? Using these transgenic mice, we have established double transgenic podocyte cell lines, which bear the podocin/rtTA, and temperature-sensitive SV40 Tag transgenes to confer conditional immortalization. These cells were found to express characteristic podocyte markers, including podocin, nephrin, and WT1. We are introducing the Vpr gene into these cells to understand Vpr-induced cell injury.? ? Many patients with podocyte diseases, including minimal change nephropathy (MCN), FSGS, and collapsing glomerulopathy are refractory to all conventional remittive therapy. We now have three open-label, phase 2 trials for podocyte diseases (current number enrolled given in parentheses): oral pulse dexamethasone for therapy-naive patients with FSGS and MCN (N=8), isotretinoin for immunotherapy-resistant patients with FSGS (N=5), and pirfenidone for patients patients with FSGS and progressive renal functional loss (N=22).? ? FSGS recurs following renal transplant in approximately 25% of patients, usually during the first 6 months and likely due to a circulating factor. We are currently studying the effect of plasma exchange plus cylosphoshphamide in treating this disorder (N=8). We are also carrying out proteomic profiling of plasma fractions obtained from patients with recurrent FSGS, in order to identify the proteins responsible for glomerular permeability.? ? The incidence of idiopathic FSGS is increased by a factor of 4 in African Americans, and the incidence of HIV-associated collapsing glomerulpathy is increased by a factor of 18 in African Americans. We are engaged in genetic studies to identify FSGS risk genes. We have found four genes to date: WT1 (Wims tumor-1), WIT1 (Wilms tumor interacting gene-1), PDSS2 (enzyme in the ubiquinone synthesis pathway) land NPHS2 (podocin).? ? A related project pursues that hypothesis that other scarring disorders which are more common in individuals of African descent are associated with genetic mutations. We have identified a number of families of diverse geographical ancestry with familial keloids, and will use genome scans to identify the responsible locus.? ? In order to identify causes of idiopathic collapsing glomerulopathy, we have initiated studies to identify possible viral causes, using blood and urine derived DNA and RNA applied to a viral gene chip.

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U.S. National Inst Diabetes/Digst/Kidney
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