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

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 5

iCTCFpod–/– mice have elevated FGF23, PTH, and an abnormal regulation of calcium and phosphate homeostasis.

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iCTCFpod–/– mice have elevated FGF23, PTH, and an abnormal regulation of...
Time course of mineral metabolism measurements in iCTCFpod–/– and WT littermate control mice. Measurements were obtained 2–8 weeks after Cre induction. (A) cFGF23 (pg/ml). n = 7, 8, 11, 10, 5, 4, 12, and 10 mice per group (left to right). (B) PTH (pg/ml). n = 6, 7, 12, 10, 7, 5, 16, and 11 mice per group (left to right). (C) FGF23 mRNA expression in calvaria from mice 8 weeks after Cre induction in increased more than 2-fold in iCTCFpod–/– mice. n = 6 WT and 5 iCTCFpod–/– mice. *P < 0.05, unpaired t test. (D) Phosphate (mg/dl). n = 6, 7, 6, 8, 6, 5, 8, and 10 mice per group (left to right). (E) Calcium (mg/dl). n = 6, 6, 6, 8, 6, 5, 8, and 10 mice per group (left to right). (F) iCa (mmol/l) was measured at 6 and 8 weeks after Cre induction. n = 6, 5, 6, and 4 mice per group (left to right). (G) Urinary phosphate (mg/24 hours) at 2, 4, and 6 weeks after Cre induction. Values were normalized to the mean phosphate excretion for WT mice at each time point. n = 7 mice for all groups. (H) 1,25(OH)2 vitamin D (pmol/l) was measured 8 weeks after Cre induction. n = 8 for both groups. ***P < 0.001, unpaired t test. Adjusted P values, controlling for multiple comparisons were calculated with a 2-way ANOVA (unless otherwise noted) and are reported as *P < 0.05, ***P < 0.001, ****P < 0.0001, comparing WT control with iCTCFpod–/– mice at each time point. Data represent the mean ± SEM. cFGF23, circulating FGF23; PTH, parathyroid hormone; iCa, ionized calcium.