Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Hanjun Wang

Abstract

Cardio-renal syndrome type 2 (CRS type 2) is defined as a chronic cardiovascular disease, usually chronic heart failure (CHF), resulting in chronic kidney disease. We hypothesized that the cardiac spinal afferent reflex (CSAR), a cardiogenic sympatho-excitatory reflex mediated by cardiac spinal afferents plays a critical role in the development of CRS type 2. We examined the effects of acute activation and chronic ablation of the CSAR on renal blood flow (RBF), renal vascular resistance (RVR), central venous pressure (CVP), renal function and renal histology in sham and myocardial infarction (MI)-induced CHF rats. RNA sequencing analysis (RNA-Seq) and validation by real-time PCR in renal tissues were used to identify the potential molecular mechanisms underlying the effects of the CSAR on renal function in CHF. We found that acute CSAR activation increased RVR to a greater extent in CHF rats compared to sham rats. Chronic CSAR ablation with the epicardial application of a selective afferent neurotoxin resiniferatoxin (RTX) at the time of myocardial infarction (MI), in part, restored RBF and reduced RVR in CHF rats. Furthermore, epicardial RTX largely prevented the development of renal dysfunction 4-5 months post-MI. RNA-Seq analysis showed that renal injury, inflammatory, hypoxia, and apoptotic genes were significantly upregulated in the renal tissue of CHF rats, which was largely restored by RTX. Renal congestion as indexed by increased CVP in CHF+vehicle rats was significantly attenuated by epicardial RTX. These data suggest that CSAR ablation by epicardial RTX has a selective protective effect on renal proximal tubular damage in the setting of CHF by partially restoring renal cortical blood flow and ameliorating renal congestion. In addition, CSAR ablation by intra-stellate ganglia (SG) injection 4 weeks after MI had similar renal protective effects on renal tubular damage in CHF rats, suggesting a translational potential of CSAR ablation in the post-MI state. To examine whether renal denervation (RDN) mimics the beneficial effects of CSAR ablation in CHF, unilateral RDN was performed in CHF rats. We observed that unilateral RDN mitigated renal dysfunction, by preventing the deterioration of glomerular filtration rate (GFR) and by attenuation of the gene expression of kidney damage marker. Unilateral RDN also improved the cardiac function of CHF rats. On the other hand, we carried out a systematic analysis of clinical trials to assess the effectiveness and risks of bilateral RDN in patients with CHF with reduced ejection fraction. Our calculation showed that RDN significantly improved the symptoms of CHF as evidenced by decreases in New York Heart Association (NYHA) class and increased six-minute walk distances. This meta-analysis also showed echocardiographic improvements in left ventricular function and congestion after RDN, suggesting that these echocardiographic improvements could drive symptomatic improvement. Moreover, RDN decreased systolic and diastolic blood pressure (BP) as well as heart rate (HR) without affecting renal function. In summary, the current study suggests that both CSAR ablation and RDN may have translational potential in the treatment of patients with CRS type 2.

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