Article ; Online: Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities.
JCI insight
2018 Volume 3, Issue 4
Abstract: ... to drive progressive CKD and osteodystrophy in the absence of interstitial fibrosis. This work introduces ... for podocyte-protective strategies for future kidney therapeutics. ... to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient ...
| Abstract | Progressive chronic kidney diseases (CKDs) are on the rise worldwide. However, the sequence of events resulting in CKD progression remain poorly understood. Animal models of CKD exploring these issues are confounded by systemic toxicities or surgical interventions to acutely induce kidney injury. Here we report the generation of a CKD mouse model through the inducible podocyte-specific ablation of an essential endogenous molecule, the chromatin structure regulator CCCTC-binding factor (CTCF), which leads to rapid podocyte loss (iCTCFpod-/-). As a consequence, iCTCFpod-/- mice develop severe progressive albuminuria, hyperlipidemia, hypoalbuminemia, and impairment of renal function, and die within 8-10 weeks. CKD progression in iCTCFpod-/- mice leads to high serum phosphate and elevations in fibroblast growth factor 23 (FGF23) and parathyroid hormone that rapidly cause bone mineralization defects, increased bone resorption, and bone loss. Dissection of the timeline leading to glomerular pathology in this CKD model led to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD and osteodystrophy in the absence of interstitial fibrosis. This work introduces an animal model with significant advantages for the study of CKD progression, and it highlights the need for podocyte-protective strategies for future kidney therapeutics. |
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| MeSH term(s) | Animals ; Bone Resorption/blood ; Bone Resorption/etiology ; Bone Resorption/pathology ; CCCTC-Binding Factor/deficiency ; CCCTC-Binding Factor/genetics ; Calcification, Physiologic/genetics ; Disease Models, Animal ; Disease Progression ; Female ; Fibroblast Growth Factors/blood ; Glomerular Filtration Rate ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Parathyroid Hormone/blood ; Podocytes/pathology ; Renal Insufficiency, Chronic/blood ; Renal Insufficiency, Chronic/complications ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/pathology |
| Chemical Substances | CCCTC-Binding Factor ; Ctcf protein, mouse ; Parathyroid Hormone ; Fibroblast Growth Factors (62031-54-3) ; fibroblast growth factor 23 (7Q7P4S7RRE) |
| Language | English |
| Publishing date | 2018-02-22 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ISSN | 2379-3708 |
| ISSN (online) | 2379-3708 |
| DOI | 10.1172/jci.insight.95091 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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