Abstract
Alport syndrome is a hereditary disease that is manifested in the eyes, ears, and kidneys. Patients with Alport syndrome die of end-stage renal failure making the kidney the most critical of the affected organs. Using a mouse model for Alport syndrome developed in this laboratory, we have investigated the mechanism of both glomerular and tubulointerstitial pathology in this disease.|Beginning in the glomerulus, we found an upregulation of matrix protein mRNA in the podocytes of Alport mice, likely explaining the origin of thickened GBM observed during disease progression. Injecting Alport mice with a soluble inhibitor for TGF-(3l delayed protein deposition. However, TGF-[U inhibition did not affect mesangial expansion or podocyte effacement, two hallmarks of Alport glomerular disease. Nor did it prevent aberrant laminin a2 deposition in the GBM of Alport mice.|Both expansion of the mesangium and podocyte effacement were significantly delayed in Alport mice lacking integrin al(3l. This receptor has been shown by in vitro studies to be involved in cell proliferation and migration. Our data support these roles in vivo. GBM deposition of laminin a2 was also delayed in Alport mice lacking integrin ocl (31 while TGF-pi inhibition in the dko mice had a synergistic effect.|By developing an Alport mouse lacking laminin a2, we were able to examine the role of this protein in Alport glomerular disease. Using electron microscopy, we found these mice to have fewer regions of thickened GBM and nearly normal podocyte foot process architecture compared to Alport mice.|In the tubulointerstitium of Alport kidneys, we discovered the colocalization of two distinct cell populations: a-smooth muscle actin-containing myofibroblasts and CD lib monocytes. We found that blocking the effects of TGF-(3 inhibited the appearance of myofibroblasts, but not monocytes, enabling us to separate the effects of these two cell populations. Deposition of matrix proteins in the tubulointerstitium was attributed to myofibroblasts. |Monocytes were found to synthesize TGF-Pl likely initiating myofibroblast accumulation. These cells were also found to make matrix-remodeling proteins. Tubular basement membranes were destroyed in regions of monocyte accumulation suggesting a role for monocytes in Alport tubular atrophy via an anoikis mechanism.