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Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Glomerular hyperfiltration and albuminuria subject the proximal tubule (PT) to a subsequent elevation of workload, growth, and hypoxia. Hypoxia plays an ambiguous role in the development and progression of DKD and shall b...

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Autores principales: Kunke, Madlen, Knöfler, Hannah, Dahlke, Eileen, Zanon Rodriguez, Luis, Böttner, Martina, Larionov, Alexey, Saudenova, Makhabbat, Ohrenschall, Gerrit M., Westermann, Magdalena, Porubsky, Stefan, Bernardes, Joana P., Häsler, Robert, Magnin, Jean-Luc, Koepsell, Hermann, Jouret, François, Theilig, Franziska
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457389/
https://www.ncbi.nlm.nih.gov/pubmed/37626062
http://dx.doi.org/10.1038/s41419-023-06074-7
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author Kunke, Madlen
Knöfler, Hannah
Dahlke, Eileen
Zanon Rodriguez, Luis
Böttner, Martina
Larionov, Alexey
Saudenova, Makhabbat
Ohrenschall, Gerrit M.
Westermann, Magdalena
Porubsky, Stefan
Bernardes, Joana P.
Häsler, Robert
Magnin, Jean-Luc
Koepsell, Hermann
Jouret, François
Theilig, Franziska
author_facet Kunke, Madlen
Knöfler, Hannah
Dahlke, Eileen
Zanon Rodriguez, Luis
Böttner, Martina
Larionov, Alexey
Saudenova, Makhabbat
Ohrenschall, Gerrit M.
Westermann, Magdalena
Porubsky, Stefan
Bernardes, Joana P.
Häsler, Robert
Magnin, Jean-Luc
Koepsell, Hermann
Jouret, François
Theilig, Franziska
author_sort Kunke, Madlen
collection PubMed
description Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Glomerular hyperfiltration and albuminuria subject the proximal tubule (PT) to a subsequent elevation of workload, growth, and hypoxia. Hypoxia plays an ambiguous role in the development and progression of DKD and shall be clarified in our study. PT-von-Hippel-Lindau (Vhl)-deleted mouse model in combination with streptozotocin (STZ)-induced type I diabetes mellitus (DM) was phenotyped. In contrary to PT-Vhl-deleted STZ-induced type 1 DM mice, proteinuria and glomerular hyperfiltration occurred in diabetic control mice the latter due to higher nitric oxide synthase 1 and sodium and glucose transporter expression. PT Vhl deletion and DKD share common alterations in gene expression profiles, including glomerular and tubular morphology, and tubular transport and metabolism. Compared to diabetic control mice, the most significantly altered in PT Vhl-deleted STZ-induced type 1 DM mice were Ldc-1, regulating cellular oxygen consumption rate, and Zbtb16, inhibiting autophagy. Alignment of altered genes in heat maps uncovered that Vhl deletion prior to STZ-induced DM preconditioned the kidney against DKD. HIF-1α stabilization leading to histone modification and chromatin remodeling resets most genes altered upon DKD towards the control level. These data demonstrate that PT HIF-1α stabilization is a hallmark of early DKD and that targeting hypoxia prior to the onset of type 1 DM normalizes renal cell homeostasis and prevents DKD development.
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spelling pubmed-104573892023-08-27 Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease Kunke, Madlen Knöfler, Hannah Dahlke, Eileen Zanon Rodriguez, Luis Böttner, Martina Larionov, Alexey Saudenova, Makhabbat Ohrenschall, Gerrit M. Westermann, Magdalena Porubsky, Stefan Bernardes, Joana P. Häsler, Robert Magnin, Jean-Luc Koepsell, Hermann Jouret, François Theilig, Franziska Cell Death Dis Article Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Glomerular hyperfiltration and albuminuria subject the proximal tubule (PT) to a subsequent elevation of workload, growth, and hypoxia. Hypoxia plays an ambiguous role in the development and progression of DKD and shall be clarified in our study. PT-von-Hippel-Lindau (Vhl)-deleted mouse model in combination with streptozotocin (STZ)-induced type I diabetes mellitus (DM) was phenotyped. In contrary to PT-Vhl-deleted STZ-induced type 1 DM mice, proteinuria and glomerular hyperfiltration occurred in diabetic control mice the latter due to higher nitric oxide synthase 1 and sodium and glucose transporter expression. PT Vhl deletion and DKD share common alterations in gene expression profiles, including glomerular and tubular morphology, and tubular transport and metabolism. Compared to diabetic control mice, the most significantly altered in PT Vhl-deleted STZ-induced type 1 DM mice were Ldc-1, regulating cellular oxygen consumption rate, and Zbtb16, inhibiting autophagy. Alignment of altered genes in heat maps uncovered that Vhl deletion prior to STZ-induced DM preconditioned the kidney against DKD. HIF-1α stabilization leading to histone modification and chromatin remodeling resets most genes altered upon DKD towards the control level. These data demonstrate that PT HIF-1α stabilization is a hallmark of early DKD and that targeting hypoxia prior to the onset of type 1 DM normalizes renal cell homeostasis and prevents DKD development. Nature Publishing Group UK 2023-08-26 /pmc/articles/PMC10457389/ /pubmed/37626062 http://dx.doi.org/10.1038/s41419-023-06074-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kunke, Madlen
Knöfler, Hannah
Dahlke, Eileen
Zanon Rodriguez, Luis
Böttner, Martina
Larionov, Alexey
Saudenova, Makhabbat
Ohrenschall, Gerrit M.
Westermann, Magdalena
Porubsky, Stefan
Bernardes, Joana P.
Häsler, Robert
Magnin, Jean-Luc
Koepsell, Hermann
Jouret, François
Theilig, Franziska
Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
title Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
title_full Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
title_fullStr Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
title_full_unstemmed Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
title_short Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
title_sort targeted deletion of von-hippel-lindau in the proximal tubule conditions the kidney against early diabetic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457389/
https://www.ncbi.nlm.nih.gov/pubmed/37626062
http://dx.doi.org/10.1038/s41419-023-06074-7
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