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

TY - JOUR

T1 - Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities

AU - Christov, Marta

AU - Clark, Abbe R

AU - Corbin, Braden

AU - Hakroush, Samy

AU - Rhee, Eugene P

AU - Saito, Hiroaki

AU - Brooks, Dan

AU - Hesse, Eric

AU - Bouxsein, Mary

AU - Galjart, Niels

AU - Jung, Ji Yong

AU - Mundel, Peter

AU - Jüppner, Harald

AU - Weins, Astrid

AU - Greka, Anna

PY - 2018/2/22

Y1 - 2018/2/22

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/jci.insight.95091

DO - 10.1172/jci.insight.95091

M3 - SCORING: Journal article

C2 - 29467330

VL - 3

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 4

ER -