Kasey Cargill1,2,3, Shelby L Hemker1,2,3, Andrew Clugston1,2,3,4, Anjana Murali1,2, Elina Mukherjee1,2, Jiao Liu5,6, Daniel Bushnell1,2, Andrew J Bodnar1,2, Zubaida Saifudeen5,6, Jacqueline Ho1,2,3, Carlton M Bates1,2,3, Dennis Kostka1,3,4, Eric S Goetzman1,3,7, Sunder Sims-Lucas8,2,3. 1. Rangos Research Center, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. 2. Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 3. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 4. Department of Developmental Biology and. 5. Section of Pediatric Nephrology, Department of Pediatrics and. 6. The Hypertension and Renal Centers of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana. 7. Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 8. Rangos Research Center, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; simslucass@upmc.edu.
Abstract
BACKGROUND: Nephron progenitors, the cell population that give rise to the functional unit of the kidney, are metabolically active and self-renew under glycolytic conditions. A switch from glycolysis to mitochondrial respiration drives these cells toward differentiation, but the mechanisms that control this switch are poorly defined. Studies have demonstrated that kidney formation is highly dependent on oxygen concentration, which is largely regulated by von Hippel-Lindau (VHL; a protein component of a ubiquitin ligase complex) and hypoxia-inducible factors (a family of transcription factors activated by hypoxia). METHODS: To explore VHL as a regulator defining nephron progenitor self-renewal versus differentiation, we bred Six2-TGCtg mice with VHLlox/lox mice to generate mice with a conditional deletion of VHL from Six2+ nephron progenitors. We used histologic, immunofluorescence, RNA sequencing, and metabolic assays to characterize kidneys from these mice and controls during development and up to postnatal day 21. RESULTS: By embryonic day 15.5, kidneys of nephron progenitor cell-specific VHL knockout mice begin to exhibit reduced maturation of nephron progenitors. Compared with controls, VHL knockout kidneys are smaller and developmentally delayed by postnatal day 1, and have about half the number of glomeruli at postnatal day 21. VHL knockout nephron progenitors also exhibit persistent Six2 and Wt1 expression, as well as decreased mitochondrial respiration and prolonged reliance on glycolysis. CONCLUSIONS: Our findings identify a novel role for VHL in mediating nephron progenitor differentiation through metabolic regulation, and suggest that VHL is required for normal kidney development.
BACKGROUND: Nephron progenitors, the cell population that give rise to the functional unit of the kidney, are metabolically active and self-renew under glycolytic conditions. A switch from glycolysis to mitochondrial respiration drives these cells toward differentiation, but the mechanisms that control this switch are poorly defined. Studies have demonstrated that kidney formation is highly dependent on oxygen concentration, which is largely regulated by von Hippel-Lindau (VHL; a protein component of a ubiquitin ligase complex) and hypoxia-inducible factors (a family of transcription factors activated by hypoxia). METHODS: To explore VHL as a regulator defining nephron progenitor self-renewal versus differentiation, we bred Six2-TGCtg mice with VHLlox/loxmice to generate mice with a conditional deletion of VHL from Six2+ nephron progenitors. We used histologic, immunofluorescence, RNA sequencing, and metabolic assays to characterize kidneys from these mice and controls during development and up to postnatal day 21. RESULTS: By embryonic day 15.5, kidneys of nephron progenitor cell-specific VHL knockout mice begin to exhibit reduced maturation of nephron progenitors. Compared with controls, VHL knockout kidneys are smaller and developmentally delayed by postnatal day 1, and have about half the number of glomeruli at postnatal day 21. VHL knockout nephron progenitors also exhibit persistent Six2 and Wt1 expression, as well as decreased mitochondrial respiration and prolonged reliance on glycolysis. CONCLUSIONS: Our findings identify a novel role for VHL in mediating nephron progenitor differentiation through metabolic regulation, and suggest that VHL is required for normal kidney development.
Authors: W M Bernhardt; R Schmitt; C Rosenberger; P M Münchenhagen; H-J Gröne; U Frei; C Warnecke; S Bachmann; M S Wiesener; C Willam; K-U Eckardt Journal: Kidney Int Date: 2006-01 Impact factor: 10.612
Authors: Andrew J Evans; Ryan C Russell; Olga Roche; T Nadine Burry; Jason E Fish; Vinca W K Chow; William Y Kim; Arthy Saravanan; Mindy A Maynard; Michelle L Gervais; Roxana I Sufan; Andrew M Roberts; Leigh A Wilson; Mark Betten; Cindy Vandewalle; Geert Berx; Philip A Marsden; Meredith S Irwin; Bin T Teh; Michael A S Jewett; Michael Ohh Journal: Mol Cell Biol Date: 2006-10-23 Impact factor: 4.272
Authors: Shelby L Hemker; Débora M Cerqueira; Andrew J Bodnar; Kasey R Cargill; Andrew Clugston; Melissa J Anslow; Sunder Sims-Lucas; Dennis Kostka; Jacqueline Ho Journal: FASEB J Date: 2020-03-05 Impact factor: 5.191
Authors: Nan Guan; Hanako Kobayashi; Ken Ishii; Olena Davidoff; Feng Sha; Talat A Ikizler; Chuan-Ming Hao; Navdeep S Chandel; Volker H Haase Journal: Kidney Int Date: 2022-03-24 Impact factor: 18.998