Progressive kidney disease is characterized by the accumulation of fibrotic mediators in the kidney. Glomerulonephritis, diabetic nephropathy, pyelonephritis, and renovascular disease together account for over 75% of patients requiring renal transplants. In these conditions it is chronic progressive renal fibrosis with associated loss of functioning nephrons that results in irreversible renal injury. While the renin angiotensin system (RAS) has traditionally been viewed as a circulating axis, evidence is accumulating that an active intrarenal RAS plays an important role in chronic kidney disease and fibrosis. Based on recent evidence reported from our lab that mast cells express and release active renin, we hypothesize that renin released from mast cells infiltrating the kidney triggers intra-renal RAS and local angiotensin (ANG II) formation. The overall objective of this proposal is addressing the important issue of whether infiltrating mast cells and mast-cell renin, play a significant role in ischemic organ damage and fibrosis. Using a model of progressive renal fibrosis (unilateral ureteral obstruction (DUO)) we will study the role of mast cell renin and local ANG II production in this process as well as investigate the role of adenosine in regulating mast cell renin gene expression. Our preliminary results demonstrate: 1. Human and rodent kidney mast cells express active renin. 2. Mast cell deficient mice do not develop renal fibrosis with UUO 3. Stabilizing mast cells in rat UUO kidney prevents renal fibrosis. 4. Inhibiting the renin released from mast cells reduces vasoconstriction in isolated and perfused kidney. 5. Stimulating the adenosine A2b receptor increases mast cell renin gene expression.
In Specific Aim I. we will characterize the molecular identity of mast cell renin and examine the effects of mast cell renin and local ANG II formation on fibrosis and vasoconstriction in UUO. These experiments will be done with mast cells isolated from human and rodent kidney and with HMC-1 cells, a cultured cell model of human mast cells. The UUO animal studies will be carried out in rat and mast cell- deficient c-Kit knockout mice and their congenic controls.
Specific Aim II. will examine regulation of mast cell renin expression, synthesis, and release by adenosine. These experiments will be done with isolated human kidney mast cells and with HMC-1 cells. If our hypothesis is proven correct then we will have identified a novel therapeutic target (mast cell renin) for ameliorating renal function in chronic kidney disease.
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