Transcriptional in Chronic Renal Disease Pathogenesis

Case Western Reserve University, Cleveland OH

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Abstract

The purpose of these studies is to identify early and causative events in pathogenic processes common to many chronic renal diseases, such as tubular cyst formation and glomerulosclerosis. We have recently identified the earliest events in pathogenesis, epithelial cell proliferation and apoptosis, in a transgenic mouse model of virus-induced chronic renal disease. These pathogenic events have been shown to occur in many increased transgene expression caused by a persistent activation of NF-kB. NF- kB is known to regulate the expression of numerous genes implicated in renal pathogenesis, and has been proposed to be a common regulatory point in establishing or accelerating disease. Thus, we hypothesize that transgene expression induces a dysregulation of NF-kB, which subsequently activates genes involved in pathogenesis, such as those controlling apoptosis. The specific aims are 1) to examine the mechanism of dysregulated NF-kB activation and its effect on gene expression in renal cells, and 2) investigate the mechanism(s) of apoptosis and the role of NF-kB in mediating apoptosis. To accomplish these studies, we have developed an in vitro system that will allow us to functionally test the regulatory role of NF-kB in mediating epithelial cell dysfunction. We will define the composition of NF-kB complexes in glomerular and tubular epithelial cells by electrophoretic mobility shift assays and western blotting. The mechanism of persistent NF-kB activation will be determined using specific inhibitors of NF-kB and dominant mutants of the critical regulatory proteins, IkBalpha and IkBbeta. The mechanism of apoptosis will be determined as well as the regulatory role of NF-kB. Thus, the long-term goal of this proposal is to better understand at the molecular level the initiating events that occur in chronic renal disease pathogenesis. An understanding of how these initiating pathogenic events are regulated may lead to the design of more effective interventional strategies.