Animals; Mice; Kidney; Kidney Tubules, Proximal; Kidney Glomerulus; Diabetic Nephropathies/genetics; Diabetes Mellitus, Type 1/complications; Diabetes Mellitus, Type 1/genetics; Diabetes Mellitus, Experimental/complications; Diabetes Mellitus, Experimental/genetics; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Immunology; Cellular and Molecular Neuroscience; Cell Biology; Cancer Research
Abstract :
[en] 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.
Disciplines :
Urology & nephrology
Author, co-author :
Kunke, Madlen; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Knöfler, Hannah; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Dahlke, Eileen; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Zanon Rodriguez, Luis; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Böttner, Martina; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Larionov, Alexey; Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland
Saudenova, Makhabbat; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Ohrenschall, Gerrit M; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Westermann, Magdalena; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany
Porubsky, Stefan; Institute of Pathology, University of Mainz, Mainz, Germany
Bernardes, Joana P; Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
Häsler, Robert; Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
Koepsell, Hermann; Institute of Anatomy and Cell Biology, Julius-Maximilians-University of Würzburg, Würzburg, Germany
Jouret, François ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
Theilig, Franziska ; Institute of Anatomy, Christian Albrechts-University Kiel, Kiel, Germany. f.theilig@anat.uni-kiel.de ; Institute of Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland. f.theilig@anat.uni-kiel.de
DFG - Deutsche Forschungsgemeinschaft [DE] Fondation de l'Association Suisse du Diabète [CH] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Helmut Horten Foundation [CH]
Funding text :
FT was supported by the DFG (CRC 877), Swiss Diabetes Foundation, and Helmut Horten Foundation. RH is supported by, Immuniverse (853995), BIOMAP (821511), miTarget (DFG, FOR 5042, P4). We thank Prof. Timo Rieg (University of Florida) for helping us with the FITC-sinistrin measurements and GFR calculation. FJ is an MD/PhD Fellow of the Fonds National de la Recherche Scientifique (FNRS) in Belgium. Open Access funding enabled and organized by Projekt DEAL.
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