Kidney disease is worldwide health problem that is becoming increasingly common. Primary glomerular disease, both genetic and acquired, represents a significant proportion of cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged, leaky to plasma proteins, and eventually non-functional. Our focus has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the filtration barrier to albumin. The GBM contains collagen IV, laminin, nidogen, and the heparan sulfate proteoglycan agrin. Mutations that affect the collagen IV component of the GBM cause Alport syndrome, or hereditary glomerulonephritis, which leads to end-stage renal disease (ESRD). The prevalence of Alport syndrome has been estimated to be 1 in 5,000 to 1 in 50,000 newborns, so there are many thousands of affected patients around the world. Structural abnormalities lead to thickening and splitting of the GBM and eventually foot process effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Until recently there had been no specific treatment for Alport syndrome. However, studies in mice and dogs had shown that ACE inhibition slows kidney disease progression to ESRD. These animal studies have been validated in human Alport syndrome, for which ACE inhibitors are now considered the standard of care. Despite this treatment breakthrough, 1) the mechanisms by which ACE inhibition slows kidney disease progression is unclear; and 2) it is still not a cure for Alport syndrome. Our preliminary data show that Alport mice with a null mutation in the albumin gene (Alb) exhibit reduced glomerulosclerosis and tubulointerstitial disease and have a prolonged lifespan. This suggests the hypothesis that albumin is injurious to podocytes and/or tubular epithelial cells by activating specific albumin-induced injury signaling pathways. The major goal of this proposal is to identify these pathways at a mechanistic level by focusing on a detailed characterization of Alport mice with and without ACEi and with levels of albumin that are normal, reduced, or zero. Identification of these injury pathways will provide novel therapeutic targets that can be modulated in parallel to inhibition of the renin-angiotensin system to further slow/inhibit progression to ESRD in Alport syndrome patients. Another important outcome of this study will be an improved understanding of the mechanism of action of ACE inhibition, whether it is effective at slowing progression to ESRD solely due to reduction in albuminuria or whether other mechanisms are involved. Our results could have important implications for understanding and treating patients with Alport syndrome and perhaps those with other kidney diseases.
Kidney disease is a huge worldwide health problem that is becoming increasingly prevalent, and primary glomerular disease, which affects the kidney's filtration apparatus, represents a significant proportion of these cases. The focus of this proposal is Alport syndrome, a hereditary glomerular disease that leads to gradual scarring of the glomeruli and eventual kidney failure. The goal of this proposal is to define the mechanisms whereby the kidney disease in these patients progresses and to determine why disease progression is slowed by ACE inhibition.
