INAPPROPRIATE ACTIVATION OF THE MINERALOCORTICOID RECEPTOR: PATHOPHYSIOLOGY AND MECHANISMS (Q3171608): Difference between revisions
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(Removed claim: summary (P836): THE MINERALOCORTICOID RECEPTOR (MR) IS A NUCLEAR RECEPTOR THAT TRANSDUCES THE EFFECTS OF ALDOSTERONE, A STEROID HORMONE PRODUCED IN THE ADRENAL CORTEX. ITS BEST CHARACTERISED ROLE IS TO INCREASE NA+ REABSORPTION AND EXCRETION OF K+ AND H+ IN DISTAL NEPHRON, BEING KEY TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND ARTERIAL PRESSURE. MR HAS MULTIPLE FUNCTIONS IN OTHER TISSUES NOT DIRECTLY RELATED TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND CAN...) |
(Created claim: summary (P836): THE MINERALOCORTICOID RECEPTOR (MR) IS A NUCLEAR RECEPTOR THAT TRANSDUCES THE EFFECTS OF ALDOSTERONE, A STEROID HORMONE PRODUCED IN THE ADRENAL CORTEX. ITS BEST CHARACTERISED ROLE IS TO INCREASE NA+ REABSORPTION AND EXCRETION OF K+ AND H+ IN DISTAL NEPHRON, BEING KEY TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND ARTERIAL PRESSURE. MR HAS MULTIPLE FUNCTIONS IN OTHER TISSUES NOT DIRECTLY RELATED TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND CAN AC...) |
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THE MINERALOCORTICOID RECEPTOR (MR) IS A NUCLEAR RECEPTOR THAT TRANSDUCES THE EFFECTS OF ALDOSTERONE, A STEROID HORMONE PRODUCED IN THE ADRENAL CORTEX. ITS BEST CHARACTERISED ROLE IS TO INCREASE NA+ REABSORPTION AND EXCRETION OF K+ AND H+ IN DISTAL NEPHRON, BEING KEY TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND ARTERIAL PRESSURE. MR HAS MULTIPLE FUNCTIONS IN OTHER TISSUES NOT DIRECTLY RELATED TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND CAN ACT AS A MEDIATOR OF THE ACTIONS OF GLUCOCORTICOIDS, HORMONES SIMILAR TO ALDOSTERONE BUT WITH A VERY DIFFERENT PHYSIOLOGICAL ROLE. EXCESSIVE ACTIVATION OF MR, EITHER BY INCREASING CIRCULATING LEVELS OF CORTICOSTEROIDS OR BY ALTERING RECEPTOR CONTROL MECHANISMS, USUALLY RESULTS IN ADVERSE EFFECTS ON THE STRUCTURE AND FUNCTION OF DIFFERENT ORGANS AND TISSUES. MR HAS AN IMPORTANT PRO-PHYBROTIC AND PRO-INFLAMMATORY ACTION IN THE CARDIOVASCULAR AND RENAL SYSTEMS, INDEPENDENT OF ITS EFFECTS ON ARTERIAL PRESSURE. MR HAS RECENTLY BEEN FOUND TO BE AN IMPORTANT FACTOR IN METABOLISM MODULATION; ITS SOBREACTIVEATION LEADS TO THE DEVELOPMENT OF OBESITY AND METABOLIC SYNDROME, WHICH TOGETHER WITH HYPERTENSION, ARE THE MAIN RISK FACTORS FOR THE DEVELOPMENT OF CARDIOVASCULAR DISEASE AND KIDNEY DAMAGE. MOREOVER, MR’S PHARMACOLOGICAL ANTAGONISM MAY LEAD TO PROBLEMS RELATED TO ELECTROLYTE HOMEOSTASIS, IN PARTICULAR HYPERKALAEMIA. THE KNOWLEDGE OF DIANA GENES MEDIATING MR’S DELETEREO EFFECTS IS STILL FRAGMENTARY. FROM A PRACTICAL POINT OF VIEW, THE IDENTIFICATION OF DIANA GENES THAT MEDIATE SEVERAL OF MR’S NEGATIVE EFFECTS SIMULTANEOUSLY IS OF PARTICULAR IMPORTANCE TO IDENTIFY NEW EFFECTIVE THERAPEUTIC TARGETS IN THE TREATMENT OF THIS SET OF CHRONIC SITUATIONS THAT LEAD TO AN INCREASE IN CARDIOVASCULAR RISK, THE LEADING CAUSE OF DEATH WORLDWIDE. IN THIS PROJECT WE PROPOSE FIRST OF ALL TO STUDY THE ROLE (SGK1), A MR DIANA GENE, AS A MEDIATOR IN THE DEVELOPMENT OF HYPERTENSION, METABOLIC SYNDROME AND KIDNEY DAMAGE (OBJECTIVE 1). LIKEWISE, WE PROPOSE TO IDENTIFY OTHER MOLECULAR DETERMINANTS OF CARDIOVASCULAR RESPONSE TO CHRONIC KIDNEY DISEASE. SPECIFICALLY, WE WILL STUDY THE ROLE OF HNRNPA2/B1 IN THE COORDINATED ALTERATION OF MR’S EXPRESSION AND ITS DIANA IONIC CHANNELS IN SMOOTH VASCULAR MUSCLE CELLS AND ENDOTHELIUM SUBJECT TO UEMIA CONDITIONS (OBJECTIVE 2). FINALLY, WE WILL EXPLORE TWO ASPECTS THAT WE BELIEVE ARE IMPORTANT IN THE ACTIVATION OF THE RECEPTOR AT THE CELLULAR AND MOLECULAR LEVEL (OBJECTIVE 3): A) THE ROLE OF THE FORMATION OF MR-DEPENDENT CYTOSOLIC SIGNAGE COMPLEXES; B) THE DETECTION OF SPECIFIC CONFORMATIONAL CHANGES OF LIGAND IN THIS RECEPTOR. AS A WHOLE, THIS PROJECT EMPLOYS A MULTIDISCIPLINARY APPROACH TO STUDY DIFFERENT LEVELS OF BIOLOGICAL ORGANISATION AND ADVANCE KNOWLEDGE OF HOW MR’S INAPPROPRIATE ACTIVATION PRODUCES ITS DIFFERENT EFFECTS THROUGH SPECIFIC DIANA GENES. THE TRANSFER OF THIS KNOWLEDGE WILL TAKE PLACE IN TWO DIRECTIONS: DIRECT THE DESIGN OF PHARMACOS AIMED AT MODULATING MR SELECTIVELY AND ON THE OTHER HAND IDENTIFY POSSIBLE THERAPEUTIC TARGETS THAT ALLOW RESTRICTING MR’S ANTAGONISM TO A COMBINATION OF CONCRETE EFFECTS THAT ATTENUATE THE DEVELOPMENT OF CARDIOVASCULAR DISEASE IN A SYNERGISTIC WAY. (English) | |||||||||||||||
| Property / summary: THE MINERALOCORTICOID RECEPTOR (MR) IS A NUCLEAR RECEPTOR THAT TRANSDUCES THE EFFECTS OF ALDOSTERONE, A STEROID HORMONE PRODUCED IN THE ADRENAL CORTEX. ITS BEST CHARACTERISED ROLE IS TO INCREASE NA+ REABSORPTION AND EXCRETION OF K+ AND H+ IN DISTAL NEPHRON, BEING KEY TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND ARTERIAL PRESSURE. MR HAS MULTIPLE FUNCTIONS IN OTHER TISSUES NOT DIRECTLY RELATED TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND CAN ACT AS A MEDIATOR OF THE ACTIONS OF GLUCOCORTICOIDS, HORMONES SIMILAR TO ALDOSTERONE BUT WITH A VERY DIFFERENT PHYSIOLOGICAL ROLE. EXCESSIVE ACTIVATION OF MR, EITHER BY INCREASING CIRCULATING LEVELS OF CORTICOSTEROIDS OR BY ALTERING RECEPTOR CONTROL MECHANISMS, USUALLY RESULTS IN ADVERSE EFFECTS ON THE STRUCTURE AND FUNCTION OF DIFFERENT ORGANS AND TISSUES. MR HAS AN IMPORTANT PRO-PHYBROTIC AND PRO-INFLAMMATORY ACTION IN THE CARDIOVASCULAR AND RENAL SYSTEMS, INDEPENDENT OF ITS EFFECTS ON ARTERIAL PRESSURE. MR HAS RECENTLY BEEN FOUND TO BE AN IMPORTANT FACTOR IN METABOLISM MODULATION; ITS SOBREACTIVEATION LEADS TO THE DEVELOPMENT OF OBESITY AND METABOLIC SYNDROME, WHICH TOGETHER WITH HYPERTENSION, ARE THE MAIN RISK FACTORS FOR THE DEVELOPMENT OF CARDIOVASCULAR DISEASE AND KIDNEY DAMAGE. MOREOVER, MR’S PHARMACOLOGICAL ANTAGONISM MAY LEAD TO PROBLEMS RELATED TO ELECTROLYTE HOMEOSTASIS, IN PARTICULAR HYPERKALAEMIA. THE KNOWLEDGE OF DIANA GENES MEDIATING MR’S DELETEREO EFFECTS IS STILL FRAGMENTARY. FROM A PRACTICAL POINT OF VIEW, THE IDENTIFICATION OF DIANA GENES THAT MEDIATE SEVERAL OF MR’S NEGATIVE EFFECTS SIMULTANEOUSLY IS OF PARTICULAR IMPORTANCE TO IDENTIFY NEW EFFECTIVE THERAPEUTIC TARGETS IN THE TREATMENT OF THIS SET OF CHRONIC SITUATIONS THAT LEAD TO AN INCREASE IN CARDIOVASCULAR RISK, THE LEADING CAUSE OF DEATH WORLDWIDE. IN THIS PROJECT WE PROPOSE FIRST OF ALL TO STUDY THE ROLE (SGK1), A MR DIANA GENE, AS A MEDIATOR IN THE DEVELOPMENT OF HYPERTENSION, METABOLIC SYNDROME AND KIDNEY DAMAGE (OBJECTIVE 1). LIKEWISE, WE PROPOSE TO IDENTIFY OTHER MOLECULAR DETERMINANTS OF CARDIOVASCULAR RESPONSE TO CHRONIC KIDNEY DISEASE. SPECIFICALLY, WE WILL STUDY THE ROLE OF HNRNPA2/B1 IN THE COORDINATED ALTERATION OF MR’S EXPRESSION AND ITS DIANA IONIC CHANNELS IN SMOOTH VASCULAR MUSCLE CELLS AND ENDOTHELIUM SUBJECT TO UEMIA CONDITIONS (OBJECTIVE 2). FINALLY, WE WILL EXPLORE TWO ASPECTS THAT WE BELIEVE ARE IMPORTANT IN THE ACTIVATION OF THE RECEPTOR AT THE CELLULAR AND MOLECULAR LEVEL (OBJECTIVE 3): A) THE ROLE OF THE FORMATION OF MR-DEPENDENT CYTOSOLIC SIGNAGE COMPLEXES; B) THE DETECTION OF SPECIFIC CONFORMATIONAL CHANGES OF LIGAND IN THIS RECEPTOR. AS A WHOLE, THIS PROJECT EMPLOYS A MULTIDISCIPLINARY APPROACH TO STUDY DIFFERENT LEVELS OF BIOLOGICAL ORGANISATION AND ADVANCE KNOWLEDGE OF HOW MR’S INAPPROPRIATE ACTIVATION PRODUCES ITS DIFFERENT EFFECTS THROUGH SPECIFIC DIANA GENES. THE TRANSFER OF THIS KNOWLEDGE WILL TAKE PLACE IN TWO DIRECTIONS: DIRECT THE DESIGN OF PHARMACOS AIMED AT MODULATING MR SELECTIVELY AND ON THE OTHER HAND IDENTIFY POSSIBLE THERAPEUTIC TARGETS THAT ALLOW RESTRICTING MR’S ANTAGONISM TO A COMBINATION OF CONCRETE EFFECTS THAT ATTENUATE THE DEVELOPMENT OF CARDIOVASCULAR DISEASE IN A SYNERGISTIC WAY. (English) / rank | |||||||||||||||
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| Property / summary: THE MINERALOCORTICOID RECEPTOR (MR) IS A NUCLEAR RECEPTOR THAT TRANSDUCES THE EFFECTS OF ALDOSTERONE, A STEROID HORMONE PRODUCED IN THE ADRENAL CORTEX. ITS BEST CHARACTERISED ROLE IS TO INCREASE NA+ REABSORPTION AND EXCRETION OF K+ AND H+ IN DISTAL NEPHRON, BEING KEY TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND ARTERIAL PRESSURE. MR HAS MULTIPLE FUNCTIONS IN OTHER TISSUES NOT DIRECTLY RELATED TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND CAN ACT AS A MEDIATOR OF THE ACTIONS OF GLUCOCORTICOIDS, HORMONES SIMILAR TO ALDOSTERONE BUT WITH A VERY DIFFERENT PHYSIOLOGICAL ROLE. EXCESSIVE ACTIVATION OF MR, EITHER BY INCREASING CIRCULATING LEVELS OF CORTICOSTEROIDS OR BY ALTERING RECEPTOR CONTROL MECHANISMS, USUALLY RESULTS IN ADVERSE EFFECTS ON THE STRUCTURE AND FUNCTION OF DIFFERENT ORGANS AND TISSUES. MR HAS AN IMPORTANT PRO-PHYBROTIC AND PRO-INFLAMMATORY ACTION IN THE CARDIOVASCULAR AND RENAL SYSTEMS, INDEPENDENT OF ITS EFFECTS ON ARTERIAL PRESSURE. MR HAS RECENTLY BEEN FOUND TO BE AN IMPORTANT FACTOR IN METABOLISM MODULATION; ITS SOBREACTIVEATION LEADS TO THE DEVELOPMENT OF OBESITY AND METABOLIC SYNDROME, WHICH TOGETHER WITH HYPERTENSION, ARE THE MAIN RISK FACTORS FOR THE DEVELOPMENT OF CARDIOVASCULAR DISEASE AND KIDNEY DAMAGE. MOREOVER, MR’S PHARMACOLOGICAL ANTAGONISM MAY LEAD TO PROBLEMS RELATED TO ELECTROLYTE HOMEOSTASIS, IN PARTICULAR HYPERKALAEMIA. THE KNOWLEDGE OF DIANA GENES MEDIATING MR’S DELETEREO EFFECTS IS STILL FRAGMENTARY. FROM A PRACTICAL POINT OF VIEW, THE IDENTIFICATION OF DIANA GENES THAT MEDIATE SEVERAL OF MR’S NEGATIVE EFFECTS SIMULTANEOUSLY IS OF PARTICULAR IMPORTANCE TO IDENTIFY NEW EFFECTIVE THERAPEUTIC TARGETS IN THE TREATMENT OF THIS SET OF CHRONIC SITUATIONS THAT LEAD TO AN INCREASE IN CARDIOVASCULAR RISK, THE LEADING CAUSE OF DEATH WORLDWIDE. IN THIS PROJECT WE PROPOSE FIRST OF ALL TO STUDY THE ROLE (SGK1), A MR DIANA GENE, AS A MEDIATOR IN THE DEVELOPMENT OF HYPERTENSION, METABOLIC SYNDROME AND KIDNEY DAMAGE (OBJECTIVE 1). LIKEWISE, WE PROPOSE TO IDENTIFY OTHER MOLECULAR DETERMINANTS OF CARDIOVASCULAR RESPONSE TO CHRONIC KIDNEY DISEASE. SPECIFICALLY, WE WILL STUDY THE ROLE OF HNRNPA2/B1 IN THE COORDINATED ALTERATION OF MR’S EXPRESSION AND ITS DIANA IONIC CHANNELS IN SMOOTH VASCULAR MUSCLE CELLS AND ENDOTHELIUM SUBJECT TO UEMIA CONDITIONS (OBJECTIVE 2). FINALLY, WE WILL EXPLORE TWO ASPECTS THAT WE BELIEVE ARE IMPORTANT IN THE ACTIVATION OF THE RECEPTOR AT THE CELLULAR AND MOLECULAR LEVEL (OBJECTIVE 3): A) THE ROLE OF THE FORMATION OF MR-DEPENDENT CYTOSOLIC SIGNAGE COMPLEXES; B) THE DETECTION OF SPECIFIC CONFORMATIONAL CHANGES OF LIGAND IN THIS RECEPTOR. AS A WHOLE, THIS PROJECT EMPLOYS A MULTIDISCIPLINARY APPROACH TO STUDY DIFFERENT LEVELS OF BIOLOGICAL ORGANISATION AND ADVANCE KNOWLEDGE OF HOW MR’S INAPPROPRIATE ACTIVATION PRODUCES ITS DIFFERENT EFFECTS THROUGH SPECIFIC DIANA GENES. THE TRANSFER OF THIS KNOWLEDGE WILL TAKE PLACE IN TWO DIRECTIONS: DIRECT THE DESIGN OF PHARMACOS AIMED AT MODULATING MR SELECTIVELY AND ON THE OTHER HAND IDENTIFY POSSIBLE THERAPEUTIC TARGETS THAT ALLOW RESTRICTING MR’S ANTAGONISM TO A COMBINATION OF CONCRETE EFFECTS THAT ATTENUATE THE DEVELOPMENT OF CARDIOVASCULAR DISEASE IN A SYNERGISTIC WAY. (English) / qualifier | |||||||||||||||
point in time: 12 October 2021
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Revision as of 18:20, 12 October 2021
Project Q3171608 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | INAPPROPRIATE ACTIVATION OF THE MINERALOCORTICOID RECEPTOR: PATHOPHYSIOLOGY AND MECHANISMS |
Project Q3171608 in Spain |
Statements
205,700.0 Euro
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242,000.0 Euro
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85.0 percent
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30 December 2016
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29 December 2020
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UNIVERSIDAD DE LA LAGUNA
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28°29'8.77"N, 16°18'57.38"W
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38023
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EL RECEPTOR DE MINERALOCORTICOIDES (MR) ES UN RECEPTOR NUCLEAR QUE TRANSDUCE LOS EFECTOS DE LA ALDOSTERONA, UNA HORMONA ESTEROIDEA PRODUCIDA EN LA CORTEZA ADRENAL. SU PAPEL MEJOR CARACTERIZADO CONSISTE EN AUMENTAR LA REABSORCION DE NA+ Y LA EXCRECION DE K+ Y H+ EN LA NEFRONA DISTAL, SIENDO CLAVE PARA LA HOMEOSTASIS DEL FLUIDO EXTRACELULAR Y PRESION ARTERIAL. MR TIENE ADEMAS MULTIPLES FUNCIONES EN OTROS TEJIDOS NO RELACIONADOS DIRECTAMENTE CON LA HOMEOSTASIS DEL FLUIDO EXTRACELULAR Y PUEDE EJERCER COMO MEDIADOR DE LAS ACCIONES DE LOS GLUCOCORTICOIDES, HORMONAS SIMILARES A LA ALDOSTERONA PERO CON UN PAPEL FISIOLOGICO MUY DIFERENTE. LA ACTIVACION EXCESIVA DE MR, YA SEA POR AUMENTO DE NIVELES CIRCULANTES DE CORTICOSTEROIDES O BIEN POR ALTERACION EN MECANISMOS DE CONTROL DEL RECEPTOR, RESULTAN GENERALMENTE EN EFECTOS ADVERSOS PARA LA ESTRUCTURA Y FUNCION DE DISTINTOS ORGANOS Y TEJIDOS. MR TIENE UNA IMPORTANTE ACCION PRO-FIBROTICA Y PRO-INFLAMATORIA EN LOS SISTEMAS CARDIOVASCULAR Y RENAL, INDEPENDIENTE DE SUS EFECTOS SOBRE LA PRESION ARTERIAL. RECIENTEMENTE, SE HA COMPROBADO QUE MR ES UN FACTOR IMPORTANTE EN LA MODULACION DEL METABOLISMO; SU SOBREACTIVACION CONDUCE AL DESARROLLO DE OBESIDAD Y SINDROME METABOLICO, QUE JUNTO CON LA HIPERTENSION, SON LOS PRINCIPALES FACTORES DE RIESGO PARA EL DESARROLLO DE ENFERMEDAD CARDIOVASCULAR Y DAÑO RENAL. POR OTRA PARTE, EL ANTAGONISMO FARMACOLOGICO DE MR PUEDE CONDUCIR A PROBLEMAS RELACIONADOS CON LA HOMEOSTASIS DE ELECTROLITOS, EN PARTICULAR HIPERPOTASEMIA. EL CONOCIMIENTO DE LOS GENES DIANA MEDIADORES DE LOS EFECTOS DELETEREOS DE MR ES TODAVIA FRAGMENTARIA. DESDE UN PUNTO DE VISTA PRACTICO, LA IDENTIFICACION DE GENES DIANA QUE SEAN MEDIADORES DE VARIOS DE LOS EFECTOS NEGATIVOS DE MR SIMULTANEAMENTE ES DE ESPECIAL IMPORTANCIA PARA IDENTIFICAR NUEVAS DIANAS TERAPEUTICAS EFICIENTES EN EL TRATAMIENTO DE ESTE CONJUNTO DE SITUACIONES CRONICAS QUE CONDUCEN A UN AUMENTO EN EL RIESGO CARDIOVASCULAR, LA PRINCIPAL CAUSA DE MUERTE A NIVEL MUNDIAL. EN ESTE PROYECTO PROPONEMOS EN PRIMER LUGAR ESTUDIAR EL PAPEL (SGK1), UN GEN DIANA DE MR , COMO MEDIADOR EN EL DESARROLLO DE HIPERTENSION, SINDROME METABOLICO Y DAÑO RENAL (OBJETIVO 1). ASI MISMO, PLANTEAMOS IDENTIFICAR OTROS DETERMINANTES MOLECULARES DE LA RESPUESTA CARDIOVASCULAR A LA ENFERMEDAD RENAL CRONICA. CONCRETAMENTE, ESTUDIAREMOS EL PAPEL DE HNRNPA2/B1 EN LA ALTERACION COORDINADA DE LA EXPRESION DE MR Y DE SUS CANALES IONICOS DIANA EN CELULAS DEL MUSCULO LISO VASCULAR Y EL ENDOTELIO SOMETIDAS A CONDICIONES DE UREMIA (OBJETIVO 2). POR ULTIMO, PROFUNDIZAREMOS EN DOS ASPECTOS QUE CREEMOS QUE SON IMPORTANTES EN LA ACTIVACION DEL RECEPTOR A NIVEL CELULAR Y MOLECULAR (OBJETIVO 3): A) EL PAPEL DE LA FORMACION DE COMPLEJOS CITOSOLICOS DE SEÑALIZACION DEPENDIENTE DE MR; B) LA DETECCION DE CAMBIOS CONFORMACIONALES ESPECIFICOS DE LIGANDO EN ESTE RECEPTOR. EN SU CONJUNTO, ESTE PROYECTO EMPLEA UNA APROXIMACION MULTIDISCIPLINAR PARA ESTUDIAR DISTINTOS NIVELES DE ORGANIZACION BIOLOGICA Y AVANZAR EN EL CONOCIMIENTO DE COMO LA ACTIVACION INAPROPIADA DE MR PRODUCE SUS DISTINTOS EFECTOS A TRAVES DE GENES DIANA CONCRETOS. EL TRASLADO DE ESTE CONOCIMIENTO SE REALIZARA EN DOS DIRECCIONES: DIRIGIR EL DISEÑO DE FARMACOS ENCAMINADOS A MODULAR MR DE FORMA SELECTIVA Y POR OTRO LADO IDENTIFICAR POSIBLES DIANAS TERAPEUTICAS QUE PERMITAN RESTRINGIR EL ANTAGONISMO DE MR A UNA COMBINACION DE EFECTOS CONCRETOS QUE DE FORMA SINERGICA ATENUEN EL DESARROLLO DE ENFERMEDAD CARDIOVASCULAR. (Spanish)
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THE MINERALOCORTICOID RECEPTOR (MR) IS A NUCLEAR RECEPTOR THAT TRANSDUCES THE EFFECTS OF ALDOSTERONE, A STEROID HORMONE PRODUCED IN THE ADRENAL CORTEX. ITS BEST CHARACTERISED ROLE IS TO INCREASE NA+ REABSORPTION AND EXCRETION OF K+ AND H+ IN DISTAL NEPHRON, BEING KEY TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND ARTERIAL PRESSURE. MR HAS MULTIPLE FUNCTIONS IN OTHER TISSUES NOT DIRECTLY RELATED TO THE HOMEOSTASIS OF EXTRACELLULAR FLUID AND CAN ACT AS A MEDIATOR OF THE ACTIONS OF GLUCOCORTICOIDS, HORMONES SIMILAR TO ALDOSTERONE BUT WITH A VERY DIFFERENT PHYSIOLOGICAL ROLE. EXCESSIVE ACTIVATION OF MR, EITHER BY INCREASING CIRCULATING LEVELS OF CORTICOSTEROIDS OR BY ALTERING RECEPTOR CONTROL MECHANISMS, USUALLY RESULTS IN ADVERSE EFFECTS ON THE STRUCTURE AND FUNCTION OF DIFFERENT ORGANS AND TISSUES. MR HAS AN IMPORTANT PRO-PHYBROTIC AND PRO-INFLAMMATORY ACTION IN THE CARDIOVASCULAR AND RENAL SYSTEMS, INDEPENDENT OF ITS EFFECTS ON ARTERIAL PRESSURE. MR HAS RECENTLY BEEN FOUND TO BE AN IMPORTANT FACTOR IN METABOLISM MODULATION; ITS SOBREACTIVEATION LEADS TO THE DEVELOPMENT OF OBESITY AND METABOLIC SYNDROME, WHICH TOGETHER WITH HYPERTENSION, ARE THE MAIN RISK FACTORS FOR THE DEVELOPMENT OF CARDIOVASCULAR DISEASE AND KIDNEY DAMAGE. MOREOVER, MR’S PHARMACOLOGICAL ANTAGONISM MAY LEAD TO PROBLEMS RELATED TO ELECTROLYTE HOMEOSTASIS, IN PARTICULAR HYPERKALAEMIA. THE KNOWLEDGE OF DIANA GENES MEDIATING MR’S DELETEREO EFFECTS IS STILL FRAGMENTARY. FROM A PRACTICAL POINT OF VIEW, THE IDENTIFICATION OF DIANA GENES THAT MEDIATE SEVERAL OF MR’S NEGATIVE EFFECTS SIMULTANEOUSLY IS OF PARTICULAR IMPORTANCE TO IDENTIFY NEW EFFECTIVE THERAPEUTIC TARGETS IN THE TREATMENT OF THIS SET OF CHRONIC SITUATIONS THAT LEAD TO AN INCREASE IN CARDIOVASCULAR RISK, THE LEADING CAUSE OF DEATH WORLDWIDE. IN THIS PROJECT WE PROPOSE FIRST OF ALL TO STUDY THE ROLE (SGK1), A MR DIANA GENE, AS A MEDIATOR IN THE DEVELOPMENT OF HYPERTENSION, METABOLIC SYNDROME AND KIDNEY DAMAGE (OBJECTIVE 1). LIKEWISE, WE PROPOSE TO IDENTIFY OTHER MOLECULAR DETERMINANTS OF CARDIOVASCULAR RESPONSE TO CHRONIC KIDNEY DISEASE. SPECIFICALLY, WE WILL STUDY THE ROLE OF HNRNPA2/B1 IN THE COORDINATED ALTERATION OF MR’S EXPRESSION AND ITS DIANA IONIC CHANNELS IN SMOOTH VASCULAR MUSCLE CELLS AND ENDOTHELIUM SUBJECT TO UEMIA CONDITIONS (OBJECTIVE 2). FINALLY, WE WILL EXPLORE TWO ASPECTS THAT WE BELIEVE ARE IMPORTANT IN THE ACTIVATION OF THE RECEPTOR AT THE CELLULAR AND MOLECULAR LEVEL (OBJECTIVE 3): A) THE ROLE OF THE FORMATION OF MR-DEPENDENT CYTOSOLIC SIGNAGE COMPLEXES; B) THE DETECTION OF SPECIFIC CONFORMATIONAL CHANGES OF LIGAND IN THIS RECEPTOR. AS A WHOLE, THIS PROJECT EMPLOYS A MULTIDISCIPLINARY APPROACH TO STUDY DIFFERENT LEVELS OF BIOLOGICAL ORGANISATION AND ADVANCE KNOWLEDGE OF HOW MR’S INAPPROPRIATE ACTIVATION PRODUCES ITS DIFFERENT EFFECTS THROUGH SPECIFIC DIANA GENES. THE TRANSFER OF THIS KNOWLEDGE WILL TAKE PLACE IN TWO DIRECTIONS: DIRECT THE DESIGN OF PHARMACOS AIMED AT MODULATING MR SELECTIVELY AND ON THE OTHER HAND IDENTIFY POSSIBLE THERAPEUTIC TARGETS THAT ALLOW RESTRICTING MR’S ANTAGONISM TO A COMBINATION OF CONCRETE EFFECTS THAT ATTENUATE THE DEVELOPMENT OF CARDIOVASCULAR DISEASE IN A SYNERGISTIC WAY. (English)
12 October 2021
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San Cristóbal de La Laguna
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Identifiers
BFU2016-78374-R
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