Abstract: SA-PO781
The Activation of BKα Channel Inhibits Cardiac Fibrosis in CKD
Session Information
- Hypertension and CVD: Mechanisms
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1503 Hypertension and CVD: Mechanisms
Authors
- Huang, Yijin, Emory University Emory College of Arts and Sciences, Atlanta, Georgia, United States
- Diop, Momar Abdou, Emory University Emory College of Arts and Sciences, Atlanta, Georgia, United States
- Bian, Shuyang, Emory University Emory College of Arts and Sciences, Atlanta, Georgia, United States
- Hassounah, Faten, Emory University School of Medicine, Atlanta, Georgia, United States
- Calvert, John W., Emory University School of Medicine, Atlanta, Georgia, United States
- Wang, Xiaonan H., Emory University School of Medicine, Atlanta, Georgia, United States
- Cai, Hui, Emory University School of Medicine, Atlanta, Georgia, United States
Background
Uremic cardiomyopathy contributes to morbidity and mortality in chronic kidney disease (CKD). Our previous study found that activation of the large conductance, calcium-activated potassium channels (BK channels) attenuated renal fibrosis in mice. We hypothesized that upregulation BK channels activity suppresses cardiac fibrosis in CKD.
Methods
CKD mice were induced by 5/6 nephrectomy. To enhance BK channel activity, BMS-191011 (10 mg/kg BW), an opener of BK channel, was given by IP injection daily for 8 weeks. Blood pressure was measured using the tail-cuff method. Echocardiogram was used to measure cardiac size and function. Cardiac myoblast cells (H9C2) were used to assess the effects of BK opener (NS1916 10mM) on fibrotic markers and TGF-β signaling pathway. The mRNA expression of BK was assayed by RT-PCR. The profibrotic protein markers were measured by western blots or immunohistochemistry (IHC) in the H9C2 cells and cardiac tissues.
Results
The expressions of BKα mRNA and protein were decreased and cardiac fibrosis was increased in the heart of CKD mice. Activation of BK channel by BMS-191011 significantly decreased the CKD-induced increase in systolic (116mmHg-CKD/BMS vs 135mmHg-CKD) and diastolic blood pressure (58mmHg-CKD/BMS vs 80mmHg-CKD) compared to the CKD groups. Echocardiogram showed that LV end-diastolic dimension increased in 5/6Nx mice (3.2mm-sham to 4.0mm-CKD), but back to normal after BK opener treatment (3.5mm-CKD/BMS; p<0.01 vs CKD) along with improving ejection fraction (63.9%-sham, 43.1%-CKD and 53.5%-CKD/BMS; p<0.05 vs CKD). IHC showed that fibrosis was significantly increased in CKD heart along with increased levels of fibronectin and vimentin, whereas BMS treatment attenuated these changes. In addition, TGF beta decreased BKα level and increased fibronectin and collagen Ia in a dose-dependent manner, whereas NS1916 inhibited the TGFβ-induced upregulation of fibronectin and collagen I in H9C2 cells.
Conclusion
Activation of BK channel by BK channel openers has significantly attenuated cardiac fibrosis in both CKD mice and in cardiac myoblast cells. This study could provide novel therapeutic strategies for treating uremic cardiomyopathy in chronic kidney diseases.
Funding
- Veterans Affairs Support