| Increasing numbers of patients present each year with end-stage renal disease. Many of the diseases causing this loss of kidney function are characterized by proteinuria, including immunoglobulin A nephropathy (IgAN) which is one of the most common causes of primary progressive glomerulonephritis. While proteinuria is known to be a negative prognostic indicator in patients with glomerular-based kidney disease, experimental evidence strongly implicates direct toxicity of proteinuria in the progression of kidney disease. The mechanism(s) by which proteinuria contributes to progressive renal injury have not been fully elucidated. Accordingly, I sought to define the role of proteinuria in IgAN, and the mechanisms by which proteinuria may contribute to kidney injury in this disease. I established that in IgAN, proteinuria---even at lower levels than previously thought---is the strongest predictor of clinical outcome. In parallel, I established an in vitro model of proteinuria and characterized the broad-based molecular response of primary human renal tubular epithelial cells to albumin exposure in this model. Using microarray technology, I defined a set of "albumin-regulated genes", and described one potential signaling mechanism by which albumin induces expression of some of these potentially injurious genes. I then explored the relevance of these findings in vivo, by studying the expression of these "albumin-regulated genes" in the tubulo-interstitial component of biopsy tissue obtained from subjects with IgAN and proteinuria, compared with the tubulo-interstitial tissue of healthy control biopsies obtained from living kidney donors. Finally, I established methods for studying gene expression in archived formalin-fixed paraffin-embedded kidney biopsies, which allowed me to confirm the relationship between the expression of a subset of these "albumin-regulated genes" and proteinuria in an independent group of biopsy samples obtained from patients with IgAN and proteinuria. Using this novel investigative approach, I have identified important potential mediators of renal injury induced by proteinuria in IgA nephropathy. |
