MECHANISMS OF AGE RELATED FIBROSIS

Vanderbilt University, Nashville TN

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Abstract

Description: (Taken directly from the application) Aging is a complex physiological condition in which the function of many organ systems becomes altered. The changes in kidney function along with progressive renal fibrosis are among the most dramatic. We have recently shown that high dose angiotensin (Ang) type 1 receptor antagonist (AT1RA) in the aged rat not only prevents ongoing age-related changes but reverses existing glomerulosclerosis, an effect linked to normalization of dysregulated extracellular matrix (ECM) metabolism and decreased plasminogen activator inhibitor-1 (PAI-1). This regression was also linked to altered cortical cell turnover, with abolishment of apoptosis. AT1 and AT2 receptors are postulated to be key in modulation of the balance of proliferation and apoptosis. In addition, cyclooxygenase-2 (COX-2) has been implicated in cell turnover in addition to arachidonic acid metabolism. COX-2 abrogates RAS responsiveness, implicating COX-2 in RAS actions. We further hypothesize that the immune system could also contribute to age-related changes. With aging, there is a decrease in antigen-stimulated immunity, and an increase in innate, i.e., macrophage-driven immunity. We hypothesize that aging changes of parenchymal cells, involving altered cell cycle proteins, lead to apoptosis, and that aging macrophages are defective in clearing these apoptotic cells. We will explore the following mechanisms of age-related renal fibrosis in studies of knockout mice with selective manipulation of macrophage vs. parenchymal cell genotype by bone marrow transplant: dysregulated ECM metabolism in aging, and the potential and mechanisms of regression of this injury; cell cycle events in aging related to the renin angiotensin system and COX-2, and their impact on injury; and the potential role of macrophages and defective clearance of apoptosis in age-related organ fibrosis.