INTERCELLULAR SIGNALING IN OBSTRUCTIVE NEPHROPATHY

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

While urinary tract obstruction is a major cause of renal insufficiency at all ages, the long-term consequences of urinary tract obstruction are more severe in the developing kidney than in the mature kidney. Following unilateral ureteral obstruction (UUO), there is marked activation of the intrarenal renin-angiotensin system, and heterogeneity in filtration among individual nephrons. The long-term consequences of chronic UUO are dependent on the balance between two nephron populations: those undergoing progressive atrophy, and those that maintain structural integrity and function. Renal tubular epithelial (RTE) cells undergo apoptosis or necrosis, leading to tubular atrophy. This is associated with progressive interstitial fibrosis and glomerular sclerosis. The aim of this project is to identify the intercellular signaling mechanisms underlying the nephron response to UUO. The following hypotheses will be tested: 1. The regional vascular response to UUO is modulated by transmission of signals from RTE cells to vascular smooth muscle and endothelial cells; 2. Apoptosis of RTE cells in response to UUO is modulated by interstitial macrophages attracted to dilated tubules by signals from RTE cells and capillary endothelial cells; 3. Interstitial fibrosis is mediated by cytokine signaling to fibroblasts and macrophages. Cellular responses to UUO will be monitored will be monitored in neonatal vs. adult rats and mice. Cellular responses to simulated UUO-injury will be studied using cell culture models. Mutant mice expressing GFP via renin promoter activation and microdissection of rats will be used to track UUO- induced alterations in renal microvascular renin expression. The role of vascular endothelial growth factor (VEGF) and its receptors will be studied in rats with UUO. The role of beta2-integrins in the renal response to UUO will be examined in beta2- integrin deficient mice. Cytokine communication between RTE cells and macrophages or interstitial fibroblasts will be monitored using in vitro models. Renal interstitial fluid will be collected from the kidneys of rats with UUO to identify the bioactive compounds increased by UUO, as well as their interstitial concentrations. The effects of these compounds (at physiologic concentrations) will then be tested in vitro. In the proposed studies, signaling molecules will be identified, quantitated and monitored for biologic effects in individual as well as co-cultured cell populations. It is likely that a better understanding of crosstalk among different renal cell populations will lead to novel interventions that reduce tubule cell death induced by ureteral obstruction. This will lead to improved outcomes in adulthood.