An update on the pathomechanisms and future therapies of Alport syndrome
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REVIEW
An update on the pathomechanisms and future therapies of Alport syndrome Damien Noone & Christoph Licht
Received: 18 April 2012 / Revised: 12 July 2012 / Accepted: 13 July 2012 / Published online: 18 August 2012 # IPNA 2012
Abstract Alport Syndrome (AS) is an inherited progressive disease that is caused by mutations of the genes encoding the key collagen chains, α3, α4, and α5, which are necessary for the composition of collagen type IV to form a robust glomerular basement membrane (GBM), capable of withstanding the significant biomechanical strain to which the glomerulus is subjected. Progressive loss of the filtration barrier allows excessive proteinuria, which ultimately leads to endstage kidney disease (ESKD). The evidence for a beneficial renoprotective effect of renin-angiotensin-aldosterone system (RAAS) blockade by angiotensin-converting enzyme (ACE) inhibition and/or angiotensin receptor blockers (ARBs) is well established in AS and recent evidence has shown that it can significantly delay the time to onset of renal replacement therapy and ESKD. Future potential treatments of AS disease progression are evaluated in this review. Keywords Alport syndrome . Proteinuria . Glomerular basement membrane . Proximal tubular epithelial cells . Tubulointerstitium . Inflammation . Fibrosis
D. Noone : C. Licht (*) Division of Nephrology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada e-mail: [email protected] C. Licht Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada C. Licht Department of Paediatrics, University of Toronto, Toronto, ON, Canada
Abbreviations ACE Angiotensin-converting enzyme AP Alternative pathway of complement activation ARB Angiotensin receptor I blocker AS Alport syndrome BMP7 Bone morphogenetic protein 7 BMT Bone marrow transplant CCL2 Chemokine (C-C Motif) ligand 2 (MCP-1) CCL5/ Chemokine (C-C Motif) ligand 5 RANTES CCR β Chemokine receptor CTGF Connective tissue growth factor CKD Chronic kidney disease CXCR α Chemokine receptor DDR Discoidin domain receptor DN Diabetic nephropathy ECM Extracellular matrix EGFR Epidermal growth factor receptor EMT Epithelial-to-mesenchymal transformation ERK Extracellular regulated kinase ESKD End-stage kidney disease GBM Glomerular basement membrane GFR Glomerular filtration rate HMG-CoA 3-Hydroxy-3-methylglutaryl CoA MAC Membrane attack complex MCP-1 Monocyte chemotactic protein-1 (CCL-2) MMP Matrix metalloproteinase MSC Mesenchymal stromal cell PPARγ Peroxisome proliferator-activated receptor γ PTEC Proximal tubular epithelial cell RAAS Renin–angiotensin–aldosterone system RANTES Regulated upon activation, normal T-cell expressed, and secreted (CCL5) TGF-β1 Transforming growth factor - β1 TNF-α Tumor necrosis factor-α XLAS X-linked Alport syndrome
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Pediatr Nephrol (2013) 28:1025–1036
glomerular basement membrane (GBM) with splitting and multilamellation of the lamina densa [2].
Introduction Alport syndrome (AS) is an inherited progressive disea
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