IgA nephropathy is a common, chronic kidney disease characterized by the deposition of lgA1-predominant immune complexes in the renal glomerulus. These complexes, whose antigens are unknown, appear early in life, and they eventually lead to glomerular injury, loss of renal function, and the need for dialysis or transplantation. Because loss of function takes decades to develop, there is an opportunity to intervene before the onset of renal insufficiency. We propose to develop a mouse model of IgA nephropathy to determine if lgA1 can be removed by injections of bacterial IgA proteases. These enzymes are endopeptidases produced by bacteria (Streptococcus, Neisseria, Haemophilus, and Clostridium species), and irrespective of their bacterial origin or catalytic mechanism, they share high substrate specificity for human lgA1 proteins. To produce the model of lgA1 deposition disease, mice will be injected with immune complexes of human lgA1, which immunofluorescence shows are deposited in the renal glomerular mesangium. Preliminary studies indicate that injections of recombinant H. influenzae IgA protease markedly reduce the glomerular burden of lgA1 in the mouse kidney. We will extend these studies to test for renal dysfunction in the mouse model, determine if IgA proteases can reverse these abnormalities, and to quantitate the effects of the protease in experiments appropriately powered for statistical analysis. We will also test a metal-dependent IgA protease from Streptococcus sanguis, an enzyme with unique attributes perhaps useful for treatment of the human illness. Finally, we will establish the elimination half-life and apparent volume of distribution of the IgA proteases in treated mice. This model of IgA nephropathy is based on human lgA1, essential for our long-term goal of removing IgA from the kidney of patients with the disease. ? ? ?
| Johnson, Troy A; Qiu, Jiazhou; Plaut, Andrew G et al. (2009) Active-site gating regulates substrate selectivity in a chymotrypsin-like serine protease the structure of haemophilus influenzae immunoglobulin A1 protease. J Mol Biol 389:559-74 |
| Lamm, Michael E; Emancipator, Steven N; Robinson, Janet K et al. (2008) Microbial IgA protease removes IgA immune complexes from mouse glomeruli in vivo: potential therapy for IgA nephropathy. Am J Pathol 172:31-6 |
