Abstract: FR-PO135
Upregulation of a Urea Transporter in Uremic Heart Promotes Cardiac Fibrosis and Increases Vimentin
Session Information
- Molecular Mechanisms of CKD - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Kuma, Akihiro, Emory University School of Medicine, Atlanta, Georgia, United States
- Klein, Janet D., Emory University, Atlanta, Georgia, United States
- Sands, Jeff M., Emory University Renal Division, Atlanta, Georgia, United States
- Wang, Xiaonan H., Emory University, Atlanta, Georgia, United States
Background
Cardiac abnormalities are linked to increased morbidity and mortality in chronic kidney disease (CKD) patients. CKD induces hypertension and retention of water, urea, and salt within the body. These are strongly related with the cardiovascular disease known as uremic cardiomyopathy. Uremic cardiomyopathy consists of left ventricular hypertrophy and interstitial fibrosis. Urea transporters (UT) are mainly involved with the urine concentrating mechanism in the kidney medulla. There is an isoform of UT-A in heart, but its role is not well known. We investigated the role of UT in mouse heart with a focus on the uremic heart.
Methods
To create a CKD model, C57BL6 mice underwent a 5/6 nephrectomy (5/6Nx), and were given 0.45-1% NaCl water to drink. Mice were sacrificed at 8 weeks after surgery. Heart tissue and blood were harvested. Mouse blood pressure measurements were determined by the tail cuff method. Cell culture studies were performed using mIMCD3 cells that were stably transfected with UT-A1. Immunohistochemistry was performed on paraffin sections. Protein expression levels were detected by western blot.
Results
BUN was 28.9 mg/dL (sham) and 56.6 mg/dL (5/6Nx) (P <0.05) proving success of the CKD model. In mouse heart, cardiac fibrosis of CKD mice was confirmed by Masson’s Trichrome staining of paraffin-sections. The protein abundance of UT-A was increased 1.4-fold and the pro-fibrosis marker vimentin was increased 1.7-fold in CKD mice vs. sham mice. Using immunohistology, we found that vimentin was also increased in CKD heart. In vitro, the amount of vimentin protein was increased 3.7-fold in UT-A1 overexpressing cells compared with empty vector control mIMCD3 cells. Both systolic blood pressure (129 mmHg (5/6Nx) vs 116 mmHg (sham)) and heart to body weight ratio; (7.18 mg/g (5/6Nx) vs 4.73 mg/g (sham)) were increased (P <0.05) in CKD mice 8 weeks after surgery.
Conclusion
The upregulation of UT-A in uremic heart was associated with an increased vimentin protein level, which could be related with increased cardiac fibrosis in chronic kidney disease.
Funding
- NIDDK Support