Abstract: SA-PO774
Elevated Left Ventricular Cardiac LIM Protein (CSRP3) in ESRD
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Hutchens, Michael, Portland VA Medical Center, Portland, Oregon, United States
- Gurley, Susan B., Oregon Health and Science University, Portland, Oregon, United States
- Eiwaz, Mahaba B., Oregon Health and Science University, Portland, Oregon, United States
- Lu, Tzongshi, Brigham and Women's Hospital, Harvard Medical School, Natick, Massachusetts, United States
- Lim, Kenneth, Massachusetts General Hospital, Boston, Massachusetts, United States
Background
Emerging evidence suggest that cardiac cytoskeletal components are involved in the pathogenesis of cardiorenal syndromes. We recently identified the cardiomyocyte transcription factor CSRP3 as an endocrine cardiorenal connector in mice. CSRP3 is a critical component of the cytoskeleton and contractile apparatus in the heart. Mutations of CSRP3 have been detected in patients with cardiomyopathy, however the role of CSRP3 in human cardiorenal disease is unknown.
Methods
We analyzed human Left Ventricular (LV) tissues from donors with end-stage renal disease (ESRD, n=15) compared to hypertensive (HTN, n=11) and healthy controls (n=18) in a 3-arm cross-sectional controlled study using The CAIN (Cardiac Aging in CKD) Cohort. All tissues underwent gross pathologic examination. LV free wall thickness (LVWT) was assessed as an index for left ventricular hypertrophy (LVH). RNASeq, immunoblotting, and qPCR were performed. Confirmatory tissue qPCR studies were performed in a rodent model of advanced nephropathy, Akita(Ins2c96y)-ReninTg (Akita-RenTg) mice and controls.
Results
Groups were well-matched and there was no statistical difference in age (ESRD 46.4±10.7; HTN 56.3±4.9; control 49.7±15.7 yrs, p=0.1) or sex (ESRD 60; HTN 64; control 58 % male, p=0.9). HTN patients had slightly higher BMI (HTN 31.5±6.6 vs ESRD 26.2±4. vs. 26.3±5.8 kg/m2, p=0.1). HTN and ESRD patients had significantly greater left ventricular wall thickness normalized to body surface area (p<0.0001). RNASeq of left ventricular tissue revealed that csrp3 is among the top 1000 genes dysregulated by ESRD. Immunoblotting for CSRP3 revealed increased LV CSRP3 in HTN patients (2.2-fold). ESRD patients had even greater levels (4.4-fold, p<0.0001) compared to controls; this was independent of LVH. These results were consistent with advanced nephropathy Akita-RenTg mice; cardiac CSRP3 mRNA was increased relative to controls (~14-fold).
Conclusion
We provide the first translational data demonstrating CSRP3 is greatly elevated in the hearts of humans with ESRD. Data from an experimental model of advanced nephropathy suggest that this cardiorenal crosstalk is conserved. We postulate that upregulation of CSRP3 may function as a stress signal in kidney failure and further studies are critically warranted to elucidate its role.
Funding
- Veterans Affairs Support