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Abstract: SA-PO201

Inducible Podocyte-Specific Deletion of CTCF Leads to Progressive CKD with Severe Bone and Mineral Disease in the Absence of Renal Fibrosis

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology


  • Christov, Marta, New York Medical College, Valhalla, New York, United States
  • Clark, Abbe Rose, Harvard University, Boston, Massachusetts, United States
  • Rhee, Eugene P., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Saito, Hiroaki, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Hesse, Eric, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Bouxsein, Mary L, Harvard Medical School, Boston, Massachusetts, United States
  • Weins, Astrid, Brigham & Women's Hospital, Boston, Massachusetts, United States
  • Mundel, Peter H, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Jüppner, Harald, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Greka, Anna, Brigham & Women's Hospital, Boston, Massachusetts, United States

Progressive chronic kidney disease (CKD) is on the rise worldwide with more than 500 million people affected. However, the sequence of events resulting in onset and progression of CKD remain poorly understood. Likewise, while FGF23 elevations are associated with increased mortality, its utility as a biomarker of early CKD remains uncertain, and whether it can be manipulated through dietary or pharmacologic interventions is controversial. Animal CKD models exploring these issues are confounded by systemic toxicities or artificial surgical interventions.


Floxed CTCF mice (CTCFfl/fl) were mated with doxycycline-inducible, podocyte-specific CRE transgenic mice (iCrepod). Treatment of Crepod-CTCFfl/fl mice with doxycycline started at 6 weeks of age to generate iCTCFpod-/- mice, and treated wild-type (WT) mice served as controls. We assessed kidney histology for podocyte loss and interstitial fibrosis, as well as mineral metabolism parameters at 2, 4, 6 and 8 weeks. We determined bone parameters by microCT and histomorphometry in iCTCFpod-/- and WT mice at 8 weeks.


We generated a novel CKD mouse model through the selective and inducible podocyte-specific deletion 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 and hypoalbuminemia, the hallmarks of the nephrotic syndrome, and die within 8-10 weeks. Progressive CKD in iCTCFpod-/- mice leads to high serum phosphate and low ionized blood calcium levels, and consequently to profound elevations in FGF23 and PTH levels that rapidly cause bone mineralization defects, increased bone resorption and bone loss.


Dissection of the timeline leading to glomerular pathology in this new CKD model led us to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD in the absence of interstitial fibrosis. This work highlights podocyte-protective strategies rather than the prevention of renal fibrosis as the most promising therapeutic approach for CKD.


  • NIDDK Support