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Published on: November 7, 2017
Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice
Yi Wang1, Linnan Bai2, Jiejun Wen1
1Department of Nephrology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Insights
Renalase (RNLS) protects the heart from chronic kidney disease (CKD) damage. Overexpressing RNLS reduces cardiac hypertrophy and fibrosis in CKD, suggesting it as a potential therapeutic target.
Area of Science:
- Cardiology
- Nephrology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) causes pathological cardiac remodeling, including myocardial hypertrophy and fibrosis.
- Current therapeutic options for CKD-induced cardiac remodeling are limited, necessitating novel therapeutic targets.
- Renalase (RNLS), a kidney-secreted protein, shows promise in renal diseases, but its cardiac protective role in CKD is unknown.
Purpose of the Study:
- To investigate the cardioprotective role of Renalase (RNLS) in the context of chronic kidney disease (CKD)-induced cardiac remodeling.
- To determine if RNLS can mitigate cardiac hypertrophy and fibrosis associated with CKD.
- To elucidate the underlying molecular mechanisms by which RNLS influences cardiac remodeling in CKD.
Main Methods:
- Utilized RNLS knockout (KO) and wild-type (WT) mice to establish CKD models.
- Employed an adeno-associated virus (AAV9) system for cardiac-specific RNLS overexpression.
- Performed echocardiography for longitudinal assessment of cardiac structure and high-throughput sequencing for mechanistic insights, with in vitro validation on cardiac fibroblasts.
Main Results:
- RNLS deficiency exacerbated CKD-induced cardiac remodeling, while cardiac-specific RNLS overexpression significantly attenuated left ventricular hypertrophy and fibrosis.
- RNA-sequencing revealed that RNLS downregulates key pathways including extracellular matrix (ECM) receptor interaction and ECM organization.
- RNLS suppressed profibrotic processes in cardiac fibroblasts, such as proliferation and epithelial-mesenchymal transition (EMT), in vitro.
Conclusions:
- RNLS demonstrates a significant cardioprotective role against CKD-induced pathological cardiac remodeling.
- RNLS exerts anti-fibrotic effects by downregulating ECM-related pathways and profibrotic cellular processes.
- RNLS represents a potential therapeutic factor for treating cardiac remodeling in CKD.
Introduction:
CKD-induced pathological cardiac remodeling is characterized by myocardial hypertrophy and cardiac fibrosis. The available therapeutic options are limited, it is thus urgently needed to identify novel therapeutic targets. Renalase (RNLS) is a newly discovered protein secreted by the kidney and was found beneficial in many renal diseases. But whether it exerts protective effects on cardiac remodeling in CKD remains unclear.
Methods:
RNLS knockout (KO) and wild-type (WT) mice were both used to build CKD models and the adeno-associated virus (AAV9) system was used to overexpress RNLS cardiac specifically. Echocardiography was performed to detect cardiac structural changes every 6 weeks until 18 weeks post-surgery. High throughput sequencing was performed to understand the underlying mechanisms and the effects of RNLS on cardiac fibroblasts were validated in vitro.
Results:
Knockout of RNLS aggravated cardiac remodeling in CKD, while RNLS cardiac-specific overexpression significantly reduced left ventricular hypertrophy and cardiac fibrosis induced by CKD. The following RNA-sequencing analysis revealed that RNLS significantly downregulated the extracellular matrix (ECM) receptor interaction pathway, ECM organization, and several ECM-related proteins. GSEA results showed RNLS significantly downregulated several profibrotic biological processes of cardiac fibroblasts which were upregulated by CKD, including fibroblast proliferation, leukocyte migration, antigen presentation, cytokine production, and epithelial-mesenchymal transition (EMT). In vitro, we validated that RNLS reduced the primary cardiac fibroblast proliferation and α-SMA expression stimulated by TGF-β.
Conclusion:
In this study, we examined the cardioprotective role of RNLS in CKD-induced cardiac remodeling. RNLS may be a potential therapeutic factor that exerts an anti-fibrotic effect in pathological cardiac remodeling.
