The mechanisms regulating blood pressure are known to have strong genetic components; however, the specific genes involved in the pathogenesis of hypertension are not well defined. Key regulators are atrial and brain natriuretic peptides (ANP, BNP) signaling through their cognate natriuretic peptide receptor-A (NPRA) and the second messenger cGMP. The ANP-BNP/NPRA system plays critical roles in the regulation of blood pressure and reno-vascular homeostasis. There is a strong association of polymorphisms in the genes that encode ANP (Nppa), BNP (Nppb), and NPRA (Npr1) with high blood pressure and cardiovascular dysfunction in humans. These phenotypes can be recapitulated using global Npr1 gene-knockout system in mice. Both male and female mice lacking global Npr1 gene (Npr1-/-) exhibit high blood pressure, but specifically male Npr1 mice suffer from hypertension, heart failure, and sudden death at adult age. It is not clear how the lack of Npr1 in the specific cell-types of kidneys and vasculature progressively leads to hypertension, nor what underlies the observed sex-differences in the global Npr1-/- mice. The Npr1 deletion exhibiting malignant hypertension in mice is significant and complements clinical findings of polymorphisms in Nppa, Nppb, and Npr1 in humans. The mechanistic understanding of how the absence of Npr1 divergently affects blood pressure in a sex-related manner remains an important yet unanswered question. We hypothesize that cell- specific deletion of Npr1 plays critical roles in the development of molecular and cellular perturbations of immunogenic and inflammatory mechanisms leading to activation of Toll-like receptors (TLRs), redox-sensitive transcription factor nuclear factor kappa B (NF-?B), adaptive T cells, and macrophages. The long-term goal of this proposal is to determine the molecular and genetic factors that contribute to immunogenic chronic inflammation leading to hypertension and reno-vascular dysfunction. The overall objective of the proposed studies is to determine the mechanistic aspects of the loss of nephron tubules (NT)- and vascular smooth muscle cell (SMC)-specific Npr1, leading to hypertension and reno-vascular remodeling and dysfunction. The central hypothesis is that the cell-specific loss of Npr1 in the kidneys and vasculature triggers the immunogenic and inflammatory processes that provoke hypertension and end-organ damage in a sex- dependent manner. The proposed specific aims will test the hypotheses: 1) the damage-associated immune receptors contribute to hypertension and reno-vascular dysfunction; 2) the down-stream redox-sensitive cascades trigger high blood pressure and renal-vascular injury and dysfunction; and 3) immunogenic mechanisms provoke hypertension, and renal-vascular disorders. The successful completion of the proposed studies could lead to the identification of much-needed new biomarkers and therapies for the treatment and prevention of hypertension and renal-vascular dysfunction in both genders in humans.
The proposed studies will utilize genetically modified mouse models to provide new insights to delineate the mechanisms of hypertension and renal and vascular injury and dysfunction in a sex-related manner. Renal and vascular functions can become severely impaired with high blood pressure leading to stroke, reno- vascular disorders, and heart failure. Both men and women can have distinct differences in progression of hypertensive disease state. The present proposal targets unique mechanisms that contribute to the molecular basis of hypertension and renal and vascular dysfunction. The findings will help in developing molecular therapeutic strategies to appropriately target treatment and prevention of hypertension and reno-vascular dysfunction in men and women.
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