Renal Denervation as a Potential Therapeutic Strategy in Cardiorenal Syndrome: An Experimental Model of Chronic Kidney Disease and Heart Failure With Pressure- And Volume-Overload

Objective: Chronic kidney disease (CKD) and heart failure (HF) often coexist, and this overlap can lead to cardiorenal syndrome (CRS), which is linked to high rates of illness and mortality. Renal denervation (RDN) is a minimally invasive, non-drug treatment that has been suggested to lower sympathetic overactivity and improve outcomes in cardiorenal syndrome (CRS). Design and method: We examined male hypertensive Fawn-hooded rats (FHH, n = 51), which are a genetic model of chronic kidney disease with high blood pressure, and compared them with normotensive Fawn-hooded rats (FHL, n = 62) used as controls. Volume overload was induced surgically by creating an aortocaval fistula (ACF), which then led to the development of HF. Phenol-based RDN was carried out 28 days later. Seventy days after RDN, the animals were euthanized, and the hearts were collected for histological and molecular analyses. Results: In ACF-FHH rats, the heart showed clear myocardial hypertrophy and fibrosis, along with increased collagen I and changes in connexin-43 (Cx43) expression, which fits with structural remodeling and a higher risk of arrhythmia. Histological analyses using Hematoxylin/Eosin and Van Gieson stains showed greater collagen deposition in the left ventricle. By comparison, ACF-FHL rats showed less severe hypertrophy and fibrosis. In FHH rats, phenol-based RDN slightly reduced collagen deposition, but it did not produce a clear change in fibrosis-related proteins (Smad2, TGF-beta), inflammatory markers (NF-kB, IL-1beta, CD68), or oxidative stress-related proteins (Nrf2, Keap1, SOD1). Survival rates were similar in the ACF-FHH group (34%) and after RDN (33%). In contrast, ACF-FHL rats had higher survival (79%), and survival increased to 90% after RDN, though this change was not statistically significant. Conclusions: In this CKD model with HF, the results suggest that RDN did not show clear heart- or kidney-protective benefits, and they point to CKD- and HF-related remodeling as a key driver of the changes observed. More studies are needed to test whether starting treatment earlier, combining treatments, or using different study models might show a clearer therapeutic benefit of RDN. This study was supported by APVV no. 21–0410, VV-MVP-24-0278; VEGA no. 2/0006/23, no. 2/0133/24; and No. LX22NPO5104.