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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 2

Progressive histopathologic changes consistent with focal and global sclerosis after podocyte ablation.

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Progressive histopathologic changes consistent with focal and global scl...
Periodic acid–Schiff staining of kidney sections from control and iCTCFpod–/– mice at 2, 4, 6, and 8 weeks after Cre induction. (A) Grossly normal-appearing glomeruli at 2 weeks with prominent protein casts visible throughout the renal cortex. (B) By 4 weeks, podocytes form adhesions to Bowman’s capsule, and protein casts are prominently present throughout the cortex and the medulla. (C) Eosinophilic segmental sclerotic lesions by 6 weeks. (D) By 8 weeks, severe global sclerosis affecting the majority of glomeruli, with dilated tubules involving primarily the renal cortex, as well as highly prominent protein casts throughout the kidney. Scale bars: 100 μm (upper panels) and 20 μm (higher-magnification lower panels).

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