Tumor necrosis factor-a (TNF) is a key cytokine involved in the pathogenesis of cardiovascular diseases. TNF could alter blood pressure by affecting multi-targets, such as cells of the immune system, the cardiovascular system, the nervous system, and the kidney. TNF can regulate the production of several downstream cytokines via activation of the nuclear factor-kB (NF-kB) signaling cascade. Our previous studies have demonstrated that TNF deficiency leads to a blunted hypertensive response and protection from kidney injury in angiotensin (Ang) II-dependent hypertension. To determine the role of kidney-derived TNF in hypertension, we transplanted kidneys from TNF-deficient (TNF KO) or wide-type (WT) donor mice to WT recipients and subjected the recipients to Ang II-dependent hypertension. The KO->WT transplant group had blunted hypertensive responses and less kidney injury compared with the WT->WT group. Therefore, we want to determine whether TNF from renal tubular epithelial cells or resident kidney macrophages contributes to the pathogenesis of Ang-dependent hypertension. To address this question, we will first assess the role of TNF derived from renal tubular cells in Ang II or DOCA-salt induced hypertension, assessing blood pressure, kidney inflammation and fibrosis in mice lacking TNF only in tubular epithelial cells (TNF KKO) and WT controls. We predict that TNF-deficiency in tubular epithelial cells will attenuate hypertensive responses and kidney injury. Our preliminary data also demonstrate resident, CX3CR1-expressing macrophages are a major source of TNF in the kidney at baseline. We will access the contribution of augmented TNF production in resident macrophages to the pathogenesis of hypertension and consequent renal injury by subjecting mice lacking TNF in resident macrophage cells (TNF MKO) mice to our hypertension models. In the near term, these studies will elucidate the major source of TNF that drives blood pressure elevation and associated target organ damage. Over the long term, our studies will identify cell-specific pathways that can be targeted to limit the progression of chronic kidney disease related to hypertension.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2018 → 06/30/2019|