ANP Receptor: Genetic and Epigenetic Mechanisms Regulating Blood Pressure and Kidney Injury and Dysfunction

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PROJECT SUMMARY The mechanisms regulating high blood pressure (BP) and kidney injury and dysfunction are known to have a strong genetic component; however, the specific genes involved in the pathogenesis of hypertension and renal disorders are not well defined. The key regulators are atrial and brain natriuretic peptides (ANP, BNP), signaling through natriuretic peptide receptor-A (NPRA) and the second messenger cGMP. There is a strong association of polymorphisms in the genes that encode ANP (Nppa), BNP (Nppb), and NPRA (Npr1) with high BP and cardiovascular disorders in humans. It is not clear how the lack of Npr1 in the specific cell- types of the kidney might progressively lead to high BP and renal disorders, nor what underlies the sex-specific differences in the disease etiologies. The genetic and epigenetic mechanisms involving transcription factors (TFs) and modified histone codes, respectively, which regulate the pathogenesis of high BP and kidney injury and dysfunction are not well understood. The preliminary and published results have provided the intriguing evidence that retinoic acid receptor-α (RAR-α) agonists enhance the transcription and expression of Npr1 and receptor signaling; however, angiotensin II (Ang II) and transforming growth factor-beta 1 (TGF-β1) repress Npr1 transcription and receptor function in primary cultured renal cells. These stimulating and inhibiting hormones also govern genetic and epigenetic mechanisms of gene expression and regulation by interacting actions of TFs and histone codes; however, their roles in modulating gene transcription and signaling in hypertension and kidney disorders are not well understood. The overall objective of the current proposal is to determine how the hormonal control mechanisms influence the genetic and epigenetic factors that govern the Npr1 and receptor function, regulating high BP and kidney injury and dysfunction in a sex-specific manner. The central hypothesis is that Npr1 expression and receptor signaling is reciprocally regulated by genetic and epigenetic mechanisms, and that the loss of cell-specific Npr1 in nephron tubules and podocytes will trigger high BP and kidney injury and disorders. The proposed specific aims will test the hypotheses: 1) determine the mechanisms that repress Npr1 expression and receptor signaling leading to high BP and kidney damage and disorders, 2) delineate the mechanisms those enhance Npr1 expression and receptor signaling and decrease high BP and kidney injury and dysfunction, and 3) delineate the interactive mechanisms those impact the divergent stimulatory and inhibitory factors regulating the paradigm shift in high BP and kidney injury and dysfunction. The findings of the completed studies should lead to the identification of much-needed new molecular biomarkers and therapies for the treatment and prevention of high BP and kidney diseases in a gender-specific manner in humans.