Abstract: SA-PO241
Activin A Inhibition Reduces Kidney Fibrosis and Normalizes Bone Abnormalities in AKI
Session Information
- CKD-MBD: Basic and Translational
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Nordholm, Anders, Department of Nephrology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
- Lodberg, Andreas, Department of Biomedicine, University of Aarhus, Aarhus, Denmark
- Snitgard Rosendal Nielsen, Simone, Clinical Cell Biology, Research Unit of Pathology, Department of Pathology, Odense University Hospital, Odense, Denmark
- Mace, Maria Lerche, Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Gravesen, Eva, Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
- Bressendorff, Iain Oshoj, Department of Nephrology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
- Morevati, Marya, Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Eijken, Marco, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Andersen, Christian Brix Folsted, Department of Biomedicine, University of Aarhus, Aarhus, Denmark
- Hornum, Mads, Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Thomsen, Jesper Skovhus, Department of Biomedicine, University of Aarhus, Aarhus, Denmark
- Andersen, Thomas Levin, Clinical Cell Biology, Research Unit of Pathology, Department of Pathology, Odense University Hospital, Odense, Denmark
- Hansen, Ditte, Department of Nephrology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
Background
Activin A inhibition (ActAi) ameliorates progressive kidney fibrosis and bone disease in CKD. In acute kidney injury (AKI) by unilateral ureter obstruction (UUO) activin A is secreted from injured kidneys leading to elevated levels in the circulation. We aimed to determine the effect of ActAi on kidney and bone in AKI.
Methods
Female C57BL/6 mice with UUO for 15 days received either ActAi with an anti-activin receptor type IIA/IIB antibody (s.c., 10mg/kg) twice weekly (UUO Ab, n=10) or vehicle (UUO Veh, n=10), while sham-operated controls received vehicle (Ctrl, n=8). At sacrifice, blood samples, kidneys, femora, and tibiae were collected. Analyses included ELISA, qPCR, histology, μCT, and bone histomorphometry.
Results
UUO Ab had reduced mRNA levels of type I collagen (20±5 vs 35±20, p<0,05) and fibronectin (8±2 vs 17±6, p<0.05) compared to UUO Veh. Histology confirmed diminished fibrosis in UUO Ab. Plasma Urea was similar in both UUO groups.
UUO Ab mice had increased volumetric bone mineral density (130±13 vs 106±11 and 103±13mg/cm3, p<0.001), and trabecular number (4.3±0.1 vs 3.9±0.2 and 3.9±0.2mm-1, p<0.001) compared to similar levels in UUO Veh and Ctrl. In UUO Veh, osteoid surface increased (OS/BS 31±14 to 43±10%, p<0.05) and quiescent surface decreased (QS/BS 13±7 to 7±3%, p<0.05) compared to Ctrl. Both were restored in UUO Ab (p<0.05). Sclerostin mRNA was reduced in UUO Veh compared to Ctrl (0.5±0.3 vs 1.1±0.4, p<0.05) but restored in in UUO Ab (0.9±0.3, p<0.05). FGF23 mRNA levels was unaffected by UUO but decreased in UUO Ab (0.4±0.2 vs 1.2±0.5 and 1.1±0.4, p<0.01). Plasma FGF23 increased in UUO Veh compared to Ctrl (50±13 vs 34±10pg/mL, p<0.05) and was normalized in UUO Ab (33±6pg/mL, p<0.01). Plasma calcium, phosphate, and PTH were similar in all groups.
Conclusion
ActAi ameliorated progressive kidney fibrosis and restored bone-forming osteoid surfaces in AKI mice, indicating a normalization of a potential mineralization defect. ActAi increased bone mineral density and microstructure as well as restored mRNA levels of osteocyte-derived sclerostin. ActAi is a promising therapeutic approach to limit AKI induced renal fibrosis and to normalize bone homeostasis.