Alport syndrome is caused by mutations in any of three type IV collagen genes(COL4A3, COL4A4, or COL4A5). The type IV collagens are found in some (but not all) basement membranes. Debilitating mutations in any of these genes results in the absence of all three proteins in the basement membranes where they are found due to an obligatory association to form heterotrimeric protomers. The disease is characterized by delayed onset progressive glomerulonephritis associated with progressive hearing loss, retinal flecks, and a weak association with aortic aneurisms. We developed a mouse model for the disease here at Boys Town that is freely available to other investigators and used world-wide to study the disease. We have used this model to determine key events that drive the progression of the glomerular disease, which includes the dysregulation of both cytokines and protease systems. We identified the key defect in the inner ear of the model to be thickening of the strial capillary basement membranes, which is again associated with disruption of both cytokine and protease systems.
More recently we have defined a key mechanism underlying the glomerular disease initiation. This mechanism involves biomechanical strain-mediated induction of a cytokine called endothelin-1, which activates receptors on the mesangial compartment of the glomerulus and induces changes in the cytoskeletal dynamics resulting in the formation of invasive filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane (GBM) which activate expression of the cytokines and protease systems known to impact the progression of the disease. When you block the endothelin A receptor using small molecules, you attenuate the disease onset and progression of the glomerular disease and prevent the thickening of the strial capillary basement membranes. Whether this results in the restoration of normal hearing and strial function is currently under investigation. The pharmacologic endothelin A receptor blocking agents are toxic, and thus unlikely to be used in children. We are currently developing biologics that should overcome the problems with toxicity.