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Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities
Marta Christov, … , Astrid Weins, Anna Greka
Marta Christov, … , Astrid Weins, Anna Greka
Published February 22, 2018
Citation Information: JCI Insight. 2018;3(4):e95091. https://doi.org/10.1172/jci.insight.95091.
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Research Article Endocrinology Nephrology

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

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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.

Authors

Marta Christov, Abbe R. Clark, Braden Corbin, Samy Hakroush, Eugene P. Rhee, Hiroaki Saito, Dan Brooks, Eric Hesse, Mary Bouxsein, Niels Galjart, Ji Yong Jung, Peter Mundel, Harald Jüppner, Astrid Weins, Anna Greka

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Figure 4

Podocyte ablation drives CKD in the absence of fibrosis.

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Podocyte ablation drives CKD in the absence of fibrosis.
(A) Trichrome s...
(A) Trichrome staining of representative sections from WT controls and iCTCFpod–/– mice at 8 weeks after Cre induction show little to no detectable interstitial fibrosis. Scale bars: 200 μm. (B) Jones methenamine silver (JMS) stain (which stains collagen, reticulin, and basement membranes black) shows only focal and subtle collagen deposition in the interstitium as well as mildly thickened tubular basement membranes in iCTCFpod–/– mice that are indistinguishable from age-matched controls. Scale bars: 100 μm. (C) Quantification of JMS staining at 6 and 8 weeks after Cre induction reveals no significant difference between WT and iCTCFpod–/– mice. (D) Detection of interstitial α-smooth muscle actin (α-SMA) staining in the kidney of an 8-week-old Cd2ap-knockout mouse with marked fibrosis serves as a positive control. Scale bar: 100 μm. (E) α-SMA staining of kidney sections at 8 weeks after Cre induction shows similar staining patterns in kidneys of WT and iCTCFpod–/– mice, with the exception of protein casts in the iCTCFpod–/– section, which stain brown in a nonspecific manner. Scale bars: 100 μm.

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ISSN 2379-3708

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