Focal Segmental Glomerulosclerosis and the Nephro6c Syndrome Dr. A. Gangji Dr. P. Marge>s
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1 Focal Segmental Glomerulosclerosis and the Nephro6c Syndrome Dr. A. Gangji Dr. P. Marge>s
2 The basic facts about proteinuria and FSGS A primer on proteinuria Endothelium and glycocalyx Podocytes Pathology of podocyte injury in FSGS Cyclosporine an old treatment with a new twist
3 Christine Chmielewski
4
5 Proteinuria basic facts Protein leaks through the glomerular filtracon barrier and is reabsorbed by the renal tubular epithelium Endothelium, basement membrane, podocytes 2-4 g albumin filtered daily, reabsorbed by tubules mg tubular proteins excreted daily
6 Satchell et al, Am J Physiol 2009
7 Glycocalyx and Type 1 Diabetes Nieuwdorp et al, Diabetes 2006
8 Proteins of the slit diaphragm Proteins of the actin cytoskeleton Anchoring proteins Holthofer NDT 2007
9 DefecCve protein idencfied in childhood nephrocc syndrome (NPHS1) as nephrin Localized to podocytes Kestila et al Mol Cell 1998 Ruotsalainen et al PNAS 1999
10 D Agati NEJM 2011
11 D Agati NEJM 2011
12 FSGS Summary of pathogenesis Primary or idiopathic Related to circulacng permeability factor GeneCc causes Secondary Drugs, infeccon, hypertension, obesity
13 FSGS Summary of pathogenesis Disease of podocytes Foot process retraccon Loss of cell to cell adhesion (nephrin, podocin, p- cadherin, ZO- 1) AlteraCon in cell cytoskeleton (synaptopodin) Podocyte detachment AXachment to basement membrane through integrins Segmental scarring Loss of filtracon funccon from that porcon of the glomeruli
14 Li et al Am J Path 2008
15 Li et al Am J Path 2008
16 Li et al Am J Path 2008
17 Epithelial mesenchymal transicon (EMT) Podocytes undergo a loss of epithelial markers and rearrangement of the cytoskeleton with upregulacon of mesenchymal markers Similar to EMT, also described as dedifferencacon Epithelial mesenchymal transicon (EMT) involves transdifferencacon of epithelial cells to mesenchymal cells central process in gastrulacon, organogenesis, metastases in cancer, and wound healing
18 Epithelial Cells Injury, growth signal Basement membrane loss of cell-cell adhesion loss of epithelial phenotype loss of cell polarity up regulation of proteases mobility, cytoskeletal reorganization αsma myofibroblast phenotype collagen deposition
19 Epithelial Mesenchymal Transition and Gastrulation It is not birth, marriage, or death, but gastrulation that is the most important event in the lifespan of an individual Lewis Wolpert Perez-Pomares, Anat Rec 2002
20 Epithelial Mesenchymal Transition Nieto, Nat Rev 2002
21 TGFβ1 induces EMT in peritoneal epithelial cells A B C Day 4 D E F Day 7 G H I Day 4 - AdDL
22 Lt renal artery PE10 Catheter Approach Perfusion Reperfusion
23 CD31 Synaptopodin GFP Ghayur et al Am J Path 2011
24 Ghayur et al Am J Path 2011
25 Ghayur et al Am J Path 2011
26 Ghayur et al Am J Path 2011
27 Li et al Am J Path 2008
28 GeneCcs of NS Machuca et al, Hum Mol Gen 2009 Remuzzi et al, JCI 2006
29 MYH9 and FSGS IniCally idencfied mutacons in non- muscle myosin heavy chain 9 (MYH9) associated with FSGS in people of African descent MYH9 is found in podocytes and is mutated in a rare condicon: Epstein Fechtner syndrome Subsequently idencfied a mutacon in apolipoprotein L1 The variant APOL1 is able to lyse a parccular subspecies of Trypanosoma brucei found in Sub- Saharan Africa
30 Permeability factor and FSGS McCarthy et al, CJASN 2011
31 GeneCcs and environment Severe (fatal) gene mutation Severe environmental injury Milder genetic mutation + environmental injury Spectrum of FSGS
32 Cyclosporine and the treatment of FSGS
33
34 Cyclosporine and the treatment of FSGS Ghayur et al Am J Path 2011
35 Summary Basic science and FSGS FSGS primary, genecc, secondary has similar pathophysiology FSGS is a disease of podocytes Podocytes undergo dedifferencacon (EMT) Detach from the basement membrane Area of detachment forms a scar Spreading of injury to other areas of the glomerulus Spectrum of genecc and environmental causes Drugs do not always work in ways we think they do
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