[vc_row][vc_column][vc_tta_accordion shape=»square» c_icon=»chevron» c_position=»right» active_section=»» no_fill=»true» collapsible_all=»true»][vc_tta_section title=»Resumen» tab_id=»resumen»][vc_column_text] The mineralocorticoid receptor (MR) is a nuclear receptor that transduces the effects of aldosterone, a steroid hormone produced in the adrenal cortex. Its best-characterized role is to increase Na+ reabsorption and K+ and H+ excretion in the distal nephron, playing a key role in extracellular fluid homeostasis and blood pressure regulation. MR also has multiple functions in other tissues not directly related to extracellular fluid homeostasis and can mediate the actions of glucocorticoids, hormones similar to aldosterone but with a very different physiological role. Excessive MR activation, whether due to increased circulating levels of corticosteroids or alterations in receptor control mechanisms, generally results in adverse effects on the structure and function of various organs and tissues. MR has a significant pro-fibrotic and pro-inflammatory effect in the cardiovascular and renal systems, independent of its effects on blood pressure. Recently, MR has been shown to be an important factor in the modulation of metabolism. Its overactivation leads to the development of obesity and metabolic syndrome, which, along with hypertension, are the main risk factors for the development of cardiovascular disease and kidney damage. Furthermore, pharmacological antagonism of MR can lead to problems related to electrolyte homeostasis, particularly hyperkalemia. Knowledge of the target genes that mediate the deleterious effects of MR is still fragmented. From a practical standpoint, identifying target genes that mediate several of the negative effects of MR simultaneously is of particular importance for identifying new, efficient therapeutic targets in the treatment of this set of chronic conditions that lead to an increased risk of cardiovascular disease, the leading cause of death worldwide. In this project, we propose, firstly, to study the role of SGK1, an MR target gene, as a mediator in the development of hypertension, metabolic syndrome, and kidney damage (objective 1). We also aim to identify other molecular determinants of the cardiovascular response to chronic kidney disease. Specifically, we will study the role of hnRNPA2/B1 in the coordinated alteration of MR expression and its target ion channels in vascular smooth muscle and endothelial cells under uremic conditions (objective 2). Finally, we will delve into two aspects that we believe are important in receptor activation at the cellular and molecular levels (objective 3): a) the role of MR-dependent cytosolic signaling complex formation; b) the detection of ligand-specific conformational changes in this receptor. Overall, this project employs a multidisciplinary approach to study different levels of biological organization and advance our understanding of how inappropriate MR activation produces its various effects through specific target genes. The transfer of this knowledge will take place in two directions: directing the design of drugs aimed at selectively modulating MR and, on the other hand, identifying possible therapeutic targets that allow restricting MR antagonism to a combination of specific effects that synergistically attenuate the development of cardiovascular disease.
[/vc_column_text][/vc_tta_section][vc_tta_section title=»Abstract» tab_id=»abstract»][vc_column_text]
The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily of transcription factors involved in the transduction of signals carried by aldosterone, a steroid hormones produced in the adrenal cortex. The best-characterized role of aldosterone/MR is to promote the reabsorption of Na+ and excretion of K+ and H+ in the distal nephron, playing a key role in electrolyte and extracellular volume homeostasis and blood pressure regulation. In addition, MR plays a variety of functions in other organs and tissues not directly involved in extracellular fluid homeostasis and mediates at least some of the effects of glucocorticoids, which are steroid hormones similar to aldosterone but with distinct physiological roles. Excess MR activity due to altered circulating levels of corticosteroids or dysregulation of mechanisms controlling their activation mostly result in deleterious effects on the structure and function of several organs and tissues. For instance, MR displays potent pro-fibrotic and pro-inflammatory effects in the cardiovascular and renal systems independently of its role in controlling blood pressure. Recently, MR role as a modulatory factor in metabolism has become apparent: excess MR activity potentiates appearance of obesity and metabolic syndrome, which together with hypertension are the most important risk factors in the development of cardiovascular disease and renal injury. It is important to note that MR antagonism may produce electrolyte imbalance, particularly hyperkalemia. Our knowledge about MR target genes mediating the deleterious effects of the receptor is still fragmentary. From a practical point of view, identifying a gene that is a common mediator of several of these effects would be especially important to identify potential therapeutic targets to efficiently treat the combination of chronic conditions that increase cardiovascular risk, the leading cause of death worldwide. In this project we propose to assess the role of SGK1, a known MR-target gene, as a mediator of hypertension, metabolic syndrome and renal injury (Aim 1). We will also identify additional molecular determinants involved in the cardiovascular response to chronic kidney disease. Specifically, we will study the role of hnRNPA2/B1 in the coordination of altered expression of MR and ion channel subunits that are modulated by this receptor in human endothelial and vascular smooth muscle cells under uremic conditions (Aim 2). Finally, we will focus on two aspects that may have a prominent role in controlling MR activation at the cellular and molecular level (Aim 3): a) the role of MR cytosolic clustering in the formation of a putative signalosome; b) characterization of MR ligand-specific structural conformations that may underlie the potency of activation or inhibition. In summary, this proposal will use a multidisciplinary approach examining different levels of biological organization to advance our knowledge on how inappropriate activation of MR leads to deleterious effects through specific target genes. Translation of this knowledge will occur in two directions: directing the design of better MR small molecule modulators and identifying new therapeutic targets that will allow to restrict MR antagonism to the desired effects in a synergistic way to slow down the progression of cardiovascular disease. [/vc_column_text][/vc_tta_section][/vc_tta_accordion][/vc_column][/vc_row]