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α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions
Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na(+) handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contrib...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220822/ https://www.ncbi.nlm.nih.gov/pubmed/34179130 http://dx.doi.org/10.3389/fcvm.2021.644797 |
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author | Guerrero, Aarón Visniauskas, Bruna Cárdenas, Pilar Figueroa, Stefanny M. Vivanco, Jorge Salinas-Parra, Nicolas Araos, Patricio Nguyen, Quynh My Kassan, Modar Amador, Cristián A. Prieto, Minolfa C. Gonzalez, Alexis A. |
author_facet | Guerrero, Aarón Visniauskas, Bruna Cárdenas, Pilar Figueroa, Stefanny M. Vivanco, Jorge Salinas-Parra, Nicolas Araos, Patricio Nguyen, Quynh My Kassan, Modar Amador, Cristián A. Prieto, Minolfa C. Gonzalez, Alexis A. |
author_sort | Guerrero, Aarón |
collection | PubMed |
description | Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na(+) handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na(+) reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na(+) reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na(+) retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca(2+) depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na(+) reabsorption. |
format | Online Article Text |
id | pubmed-8220822 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82208222021-06-24 α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions Guerrero, Aarón Visniauskas, Bruna Cárdenas, Pilar Figueroa, Stefanny M. Vivanco, Jorge Salinas-Parra, Nicolas Araos, Patricio Nguyen, Quynh My Kassan, Modar Amador, Cristián A. Prieto, Minolfa C. Gonzalez, Alexis A. Front Cardiovasc Med Cardiovascular Medicine Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na(+) handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na(+) reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na(+) reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na(+) retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca(2+) depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na(+) reabsorption. Frontiers Media S.A. 2021-06-04 /pmc/articles/PMC8220822/ /pubmed/34179130 http://dx.doi.org/10.3389/fcvm.2021.644797 Text en Copyright © 2021 Guerrero, Visniauskas, Cárdenas, Figueroa, Vivanco, Salinas-Parra, Araos, Nguyen, Kassan, Amador, Prieto and Gonzalez. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cardiovascular Medicine Guerrero, Aarón Visniauskas, Bruna Cárdenas, Pilar Figueroa, Stefanny M. Vivanco, Jorge Salinas-Parra, Nicolas Araos, Patricio Nguyen, Quynh My Kassan, Modar Amador, Cristián A. Prieto, Minolfa C. Gonzalez, Alexis A. α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions |
title | α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions |
title_full | α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions |
title_fullStr | α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions |
title_full_unstemmed | α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions |
title_short | α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na(+) Reabsorption During High Glucose Conditions |
title_sort | α-ketoglutarate upregulates collecting duct (pro)renin receptor expression, tubular angiotensin ii formation, and na(+) reabsorption during high glucose conditions |
topic | Cardiovascular Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220822/ https://www.ncbi.nlm.nih.gov/pubmed/34179130 http://dx.doi.org/10.3389/fcvm.2021.644797 |
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