Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities

JCI Insight
Marta ChristovAnna Greka

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 intro...Continue Reading

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Citations

Mar 5, 2020·Journal of Nephrology·Annet Bouma-de Krijger, Marc G Vervloet
May 18, 2018·Frontiers in Endocrinology·Beatrice Richter, Christian Faul
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Mar 2, 2021·The Journal of Clinical Investigation·Robert Safirstein
Aug 7, 2021·Cellular and Molecular Gastroenterology and Hepatology·Yeeun ChoiHyoung-Pyo Kim

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Methods Mentioned

BETA
protein casts
electron microscopy
biopsies
urine collection
ELISA
light microscopy
reverse-phase chromatography

Software Mentioned

ImageJ
Scanco μCT Evaluation Program
PRISM
GraphPad
Osteomeasure

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