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Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease
Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819747/ https://www.ncbi.nlm.nih.gov/pubmed/33170807 http://dx.doi.org/10.1172/jci.insight.140483 |
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author | Cansby, Emmelie Caputo, Mara Gao, Lei Kulkarni, Nagaraj M. Nerstedt, Annika Ståhlman, Marcus Borén, Jan Porosk, Rando Soomets, Ursel Pedrelli, Matteo Parini, Paolo Marschall, Hanns-Ulrich Nyström, Jenny Howell, Brian W. Mahlapuu, Margit |
author_facet | Cansby, Emmelie Caputo, Mara Gao, Lei Kulkarni, Nagaraj M. Nerstedt, Annika Ståhlman, Marcus Borén, Jan Porosk, Rando Soomets, Ursel Pedrelli, Matteo Parini, Paolo Marschall, Hanns-Ulrich Nyström, Jenny Howell, Brian W. Mahlapuu, Margit |
author_sort | Cansby, Emmelie |
collection | PubMed |
description | Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression. |
format | Online Article Text |
id | pubmed-7819747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-78197472021-01-25 Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease Cansby, Emmelie Caputo, Mara Gao, Lei Kulkarni, Nagaraj M. Nerstedt, Annika Ståhlman, Marcus Borén, Jan Porosk, Rando Soomets, Ursel Pedrelli, Matteo Parini, Paolo Marschall, Hanns-Ulrich Nyström, Jenny Howell, Brian W. Mahlapuu, Margit JCI Insight Research Article Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression. American Society for Clinical Investigation 2020-12-17 /pmc/articles/PMC7819747/ /pubmed/33170807 http://dx.doi.org/10.1172/jci.insight.140483 Text en © 2020 Cansby et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Cansby, Emmelie Caputo, Mara Gao, Lei Kulkarni, Nagaraj M. Nerstedt, Annika Ståhlman, Marcus Borén, Jan Porosk, Rando Soomets, Ursel Pedrelli, Matteo Parini, Paolo Marschall, Hanns-Ulrich Nyström, Jenny Howell, Brian W. Mahlapuu, Margit Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
title | Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
title_full | Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
title_fullStr | Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
title_full_unstemmed | Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
title_short | Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
title_sort | depletion of protein kinase stk25 ameliorates renal lipotoxicity and protects against diabetic kidney disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819747/ https://www.ncbi.nlm.nih.gov/pubmed/33170807 http://dx.doi.org/10.1172/jci.insight.140483 |
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