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JCI Insight DOI:10.1172/jci.insight.95091

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

Publication TypeJournal Article
Year of Publication2018
AuthorsChristov, M, Clark, AR, Corbin, B, Hakroush, S, Rhee, EP, Saito, H, Brooks, D, Hesse, E, Bouxsein, M, Galjart, N, Jung, JYong, Mundel, P, Jüppner, H, Weins, A, Greka, A
JournalJCI Insight
Volume3
Issue4
Date Published2018 Feb 22
ISSN2379-3708
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.

DOI10.1172/jci.insight.95091
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29467330?dopt=Abstract

Alternate JournalJCI Insight
PubMed ID29467330
PubMed Central IDPMC5916242
Grant ListR01 DK057683 / DK / NIDDK NIH HHS / United States
K08 DK093783 / DK / NIDDK NIH HHS / United States
F31 CA195701 / CA / NCI NIH HHS / United States
R01 DK095045 / DK / NIDDK NIH HHS / United States
R01 DK099465 / DK / NIDDK NIH HHS / United States
R01 DK046718 / DK / NIDDK NIH HHS / United States
R03 DK107918 / DK / NIDDK NIH HHS / United States
R01 DK091218 / DK / NIDDK NIH HHS / United States
R56 DK046718 / DK / NIDDK NIH HHS / United States
K08 DK083511 / DK / NIDDK NIH HHS / United States
R01 DK062472 / DK / NIDDK NIH HHS / United States
R56 DK093746 / DK / NIDDK NIH HHS / United States
R37 DK046718 / DK / NIDDK NIH HHS / United States
P30 AR066261 / AR / NIAMS NIH HHS / United States
K08 DK093608 / DK / NIDDK NIH HHS / United States
P01 DK011794 / DK / NIDDK NIH HHS / United States