Our proposal seeks to investigate the impact of angiotensin (Ang) II on the aging kidney and tubulointerstitial fibrosis, a mechanism that correlates with progressive kidney disease in aging. Tubulointerstitial fibrosis is the predominant histomorphologic finding that predicts progression of clinical kidney disease. Sufficient data exist to support that blockade of the Ang II type 1 receptor (AT1R) has been shown to improve tubulointerstitial fibrosis and progression of kidney disease;however, the burden of CKD and ESRD remains high in our elderly despite widespread use of AT1R blockade. This highlights the need to investigate strategies to prevent progressive CKD. In this context, there has been tremendous interest in targeting reductions in mammalian Target of Rapamycin (mTOR)/S6K1 activity to improve tubulointerstitial fibrosis and kidney function in polycystic and diabetic kidney disease models. mTOR holds a strategic position at the nexus of nutrient/stress sensing pathways that contribute to the importance of TOR/S6K1 function in regulating chronic disease and in aging. Our preliminary data suggest that Ang II contributes directly to activation of mTOR and S6K1 resulting in tubulointerstitial fibrosis. Our data further suggest the mechanism occurs through loss of adhesion molecules such as the proximal tubule specific N-cadherin and promotion of epithelial-mesynchymal transition (EMT). Cadherin loss is a critical first step in tubulointerstitial fibrosis through EMT. Understanding of agonists that elicit EMT and loss of adhesion are limited in tubulointerstitial fibrosis and progressive kidney disease, especially in the context of aging. Thereby, this preclinical proposal broadly serves to investigate a novel mechanism that serves a significant area of clinical need with interventions that have direct clinical relevance.
Our aims have been developed to target early tubulointerstitial fibrosis in order to prevent progressive kidney disease in aging. In our work proposed, in Specific Aim I we will examine the role of Ang II activation of mTOR/S6K1 and loss of the proximal tubule specific adhesion molecule N-cadherin in relation to EMT and tubulointerstitial fibrosis in progressive kidney disease in an aging rodent model. We will then explore activation/phosphorylation of mTOR and S6K1 and the novel role for loss of N-cadherin expression in early stage tubulointerstitial fibrosis on histomorphologic and immunohistochemical analysis as well as EMT via ultrastructural analysis with transmission electron microscopy. To further explore the specific role of mTOR/S6K1 roles on N-cadherin loss, in Specific Aim 2 we will focus on utilization of knockdown strategies with RNA silencing to delineate the specific complex within the proximal tubule that dictates loss of N-cadherin. We propose RNAi of AT1R, mTORC1/S6K1 in primary culture of aging proximal tubule cells and measure N-cadherin in conjunction with specific markers of EMT and fibrosis.

Public Health Relevance

Aging is a leading risk factor for kidney disease and care for chronic kidney disease (CKD) and end-stage renal disease (ESRD) is one of the leading healthcare expenditures in the US. Tubulointerstitial fibrosis is the predominant finding that predicts progression of kidney disease. However, our understanding of mechanisms that elicit fibrosis and progressive kidney disease in aging remain limited. This highlights the need to investigate strategies that interrupt this mechanism at early stages to prevent progressive CKD in the aging population. Thereby, our proposal seeks to investigate a novel mechanism that contributes to the early development of tubulointerstitial fibrosis with interruptions schemes that have direct clinical relevance.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
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Murthy, Mahadev
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University of Missouri-Columbia
Internal Medicine/Medicine
Schools of Medicine
United States
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