Unknown

Dataset Information

0

Wnt/?-catenin signaling mediates both heart and kidney injury in type 2 cardiorenal syndrome.


ABSTRACT: In type 2 cardiorenal syndrome, chronic heart failure is thought to cause or promote chronic kidney disease; however, the underlying mechanisms remain poorly understood. We investigated the role of Wnt signaling in heart and kidney injury in a mouse model of cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC). At 8 weeks after TAC, cardiac hypertrophy, inflammation, and fibrosis were prominent, and echocardiography confirmed impaired cardiac function. The cardiac lesions were accompanied by upregulation of multiple Wnt ligands and activation of ?-catenin, as well as activation of the renin-angiotensin system (RAS). Wnt3a induced multiple components of the RAS in primary cardiomyocytes and cardiac fibroblasts in vitro. TAC also caused proteinuria and kidney fibrosis, accompanied by klotho depletion and ?-catenin activation in the kidney. Pharmacologic blockade of ?-catenin with a small molecule inhibitor or the RAS with losartan ameliorated cardiac injury, restored heart function, and mitigated the renal lesions. Serum from TAC mice was sufficient to activate ?-catenin and trigger tubular cell injury in vitro, indicating a role for circulating factors. Multiple inflammatory cytokines were upregulated in the circulation of TAC mice, and tumor necrosis factor-? was able to inhibit klotho, induce ?-catenin activation, and cause tubular cell injury in vitro. These studies identify Wnt/?-catenin signaling as a common pathogenic mediator of heart and kidney injury in type 2 cardiorenal syndrome after TAC. Targeting this pathway could be a promising therapeutic strategy to protect both organs in cardiorenal syndrome.

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC6431558 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC5997634 | BioStudies
2020-01-01 | S-EPMC7150840 | BioStudies
2019-01-01 | S-EPMC6949099 | BioStudies
1000-01-01 | S-EPMC6251653 | BioStudies
1000-01-01 | S-EPMC5595838 | BioStudies
2017-01-01 | S-EPMC5592833 | BioStudies
1000-01-01 | S-EPMC4279741 | BioStudies
2019-01-01 | S-EPMC6431566 | BioStudies
2019-01-01 | S-EPMC6718575 | BioStudies
1000-01-01 | S-EPMC3261567 | BioStudies