title: Feasibility of repairing glomerular basement membrane defects in Alport syndrome.
abstract: Alport syndrome is a hereditary glomerular disease that leads to kidney failure. It is caused by mutations affecting one of three chains of the collagen α3α4α5(IV) heterotrimer, which forms the major collagen IV network of the glomerular basement membrane (GBM). In the absence of the α3α4α5(IV) network, the α1α1α2(IV) network substitutes, but it is insufficient to maintain normal kidney function. Inhibition of angiotensin-converting enzyme slows progression to kidney failure in patients with Alport syndrome but is not a cure. Restoration of the normal collagen α3α4α5(IV) network in the GBM, by either cell- or gene-based therapy, is an attractive and logical approach toward a cure, but whether or not the abnormal GBM can be repaired once it has formed and is functioning is unknown. Using a mouse model of Alport syndrome and an inducible transgene system, we found that secretion of α3α4α5(IV) heterotrimers by podocytes into a preformed, abnormal, filtering Alport GBM is effective at restoring the missing collagen IV network, slowing kidney disease progression, and extending life span. This proof-of-principle study demonstrates the plasticity of the mature GBM and validates the pursuit of therapeutic approaches aimed at normalizing the GBM to prolong kidney function.
authors.affiliation: Renal Division and.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lin
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Suh
authors.forename: Gloriosa
authors.initials: G
authors.lastname: Go
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000502:physiology; D001485:Basement Membrane / Q000503:physiopathology*; D024141:Collagen Type IV / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005240:Feasibility Studies; D006801:Humans; D007678:Kidney Glomerulus / Q000503:physiopathology*; D051379:Mice; D009394:Nephritis, Hereditary / Q000503:physiopathology* / Q000628:therapy; D022661:RNA, Untranslated / Q000502:physiology; D019076:Transgenes
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D022661:RNA, Untranslated; C057112:type IV collagen alpha3 chain