Kidney Week

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

Authors

• Christov, Marta, New York Medical College, Valhalla, New York, United States

Marta Christov,

• Clark, Abbe Rose, Harvard University, Boston, Massachusetts, United States

Abbe Rose Clark,

• Rhee, Eugene P., Massachusetts General Hospital, Boston, Massachusetts, United States

Eugene P. Rhee,

• Saito, Hiroaki, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Hiroaki Saito,

• Hesse, Eric, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Eric Hesse,

• Bouxsein, Mary L, Harvard Medical School, Boston, Massachusetts, United States

Mary L Bouxsein,

• Weins, Astrid, Brigham & Women's Hospital, Boston, Massachusetts, United States

Astrid Weins,

• Mundel, Peter H, Goldfinch Bio, Cambridge, Massachusetts, United States

Peter H Mundel,

• Jüppner, Harald, Massachusetts General Hospital, Boston, Massachusetts, United States

Harald Jüppner,

• Greka, Anna, Brigham & Women's Hospital, Boston, Massachusetts, United States

Anna Greka,

Background

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.

Methods

Floxed CTCF mice (CTCF^fl/fl) were mated with doxycycline-inducible, podocyte-specific CRE transgenic mice (iCre^pod). Treatment of Cre^pod-CTCF^fl/fl mice with doxycycline started at 6 weeks of age to generate iCTCF^pod-/- 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 iCTCF^pod-/- and WT mice at 8 weeks.

Results

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 (iCTCF^pod-/-). As a consequence, iCTCF^pod-/- mice develop severe progressive albuminuria, hyperlipidemia and hypoalbuminemia, the hallmarks of the nephrotic syndrome, and die within 8-10 weeks. Progressive CKD in iCTCF^pod-/- 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.

Conclusion

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.

Funding

• NIDDK Support