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Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice

Insulin facilitates renal sodium reabsorption and attenuates gluconeogenesis. Sex differences in this regulation have not been well characterized. Using tetracycline-inducible Cre-lox recombination, we knocked out (KO) the insulin receptor (InsR) from the renal tubule in adult male (M) and female (F...

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Autores principales: Sohail, Soha, Akkawi, Gabriella, Rechter, Taylor, Fluitt, Maurice B., Ecelbarger, Carolyn M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178497/
https://www.ncbi.nlm.nih.gov/pubmed/37175762
http://dx.doi.org/10.3390/ijms24098056
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author Sohail, Soha
Akkawi, Gabriella
Rechter, Taylor
Fluitt, Maurice B.
Ecelbarger, Carolyn M.
author_facet Sohail, Soha
Akkawi, Gabriella
Rechter, Taylor
Fluitt, Maurice B.
Ecelbarger, Carolyn M.
author_sort Sohail, Soha
collection PubMed
description Insulin facilitates renal sodium reabsorption and attenuates gluconeogenesis. Sex differences in this regulation have not been well characterized. Using tetracycline-inducible Cre-lox recombination, we knocked out (KO) the insulin receptor (InsR) from the renal tubule in adult male (M) and female (F) mice (C57Bl6 background) with a paired box 8 (PAX8) promoter. Body weights were not affected by the KO, but mean kidney weights were reduced in the KO mice (13 and 3%, in M and F, respectively, relative to wild-type (WT) mice). A microscopic analysis revealed 25 and 19% reductions in the proximal tubule (PT) and cortical collecting duct cell heights, respectively, in KOMs relative to WTMs. The reductions were 5 and 11% for KOFs. Western blotting of renal cortex homogenates showed decreased protein levels for the β and γ subunits of the epithelial sodium channel (ENaC) and the sodium-potassium-2-chloride cotransporter type 2 (NKCC2) in both sexes of KO mice; however, α-ENaC was upregulated in KOMs and downregulated in KOFs. Both sexes of KO mice cleared exogenously administered glucose faster than the WT mice and had lower semi-fasted, anesthetized blood glucose levels. However, KOMs (but not KOFs) demonstrated evidence of enhanced renal gluconeogenesis, including higher levels of renal glucose-6-phosphatase, the PT’s production of glucose, post-prandial blood glucose, and plasma insulin, whereas KOFs exhibited downregulation of renal high-capacity sodium glucose cotransporter (SGLT2) and upregulation of SGLT1; these changes appeared to be absent in the KOM. Overall, these findings suggest a sex-differential reliance on intact renal tubular InsR signaling which may be translationally important in type 2 diabetes, obesity, or insulin resistance when renal insulin signaling is reduced.
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spelling pubmed-101784972023-05-13 Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice Sohail, Soha Akkawi, Gabriella Rechter, Taylor Fluitt, Maurice B. Ecelbarger, Carolyn M. Int J Mol Sci Article Insulin facilitates renal sodium reabsorption and attenuates gluconeogenesis. Sex differences in this regulation have not been well characterized. Using tetracycline-inducible Cre-lox recombination, we knocked out (KO) the insulin receptor (InsR) from the renal tubule in adult male (M) and female (F) mice (C57Bl6 background) with a paired box 8 (PAX8) promoter. Body weights were not affected by the KO, but mean kidney weights were reduced in the KO mice (13 and 3%, in M and F, respectively, relative to wild-type (WT) mice). A microscopic analysis revealed 25 and 19% reductions in the proximal tubule (PT) and cortical collecting duct cell heights, respectively, in KOMs relative to WTMs. The reductions were 5 and 11% for KOFs. Western blotting of renal cortex homogenates showed decreased protein levels for the β and γ subunits of the epithelial sodium channel (ENaC) and the sodium-potassium-2-chloride cotransporter type 2 (NKCC2) in both sexes of KO mice; however, α-ENaC was upregulated in KOMs and downregulated in KOFs. Both sexes of KO mice cleared exogenously administered glucose faster than the WT mice and had lower semi-fasted, anesthetized blood glucose levels. However, KOMs (but not KOFs) demonstrated evidence of enhanced renal gluconeogenesis, including higher levels of renal glucose-6-phosphatase, the PT’s production of glucose, post-prandial blood glucose, and plasma insulin, whereas KOFs exhibited downregulation of renal high-capacity sodium glucose cotransporter (SGLT2) and upregulation of SGLT1; these changes appeared to be absent in the KOM. Overall, these findings suggest a sex-differential reliance on intact renal tubular InsR signaling which may be translationally important in type 2 diabetes, obesity, or insulin resistance when renal insulin signaling is reduced. MDPI 2023-04-29 /pmc/articles/PMC10178497/ /pubmed/37175762 http://dx.doi.org/10.3390/ijms24098056 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sohail, Soha
Akkawi, Gabriella
Rechter, Taylor
Fluitt, Maurice B.
Ecelbarger, Carolyn M.
Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice
title Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice
title_full Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice
title_fullStr Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice
title_full_unstemmed Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice
title_short Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice
title_sort sex modulates response to renal-tubule-targeted insulin receptor deletion in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178497/
https://www.ncbi.nlm.nih.gov/pubmed/37175762
http://dx.doi.org/10.3390/ijms24098056
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