Aggravated endothelial endocrine dysfunction and intimal thickening of renal artery in high-fat diet-induced obese pigs following renal denervation

Abstract

Background: Renal denervation (RDN) targeting the sympathetic nerves in the renal arterial adventitia as a treatment of resistant hypertension can cause endothelial injury and vascular wall injury. This study aims to evaluate the risk of atherosclerosis induced by RDN in renal arteries. Methods: A total of 15 minipigs were randomly assigned to 3 groups: (1) control group, (2) sham group, and (3) RDN group (n = 5 per group). All pigs were fed a high-fat diet (HFD) for 6 months after appropriate treatment. The degree of intimal thickening of renal artery and the conversion of endothelin 1 (ET-1) receptors were evaluated by histological staining. Western blot was used to assess the expression of nitric oxide (NO) synthesis signaling pathway, ET-1 and its receptors, NADPH oxidase 2 (NOX2) and 4-hydroxynonenal (4-HNE) proteins, and the activation of NF-kappa B (NF-κB). Results: The histological staining results suggested that compared to the sham treatment, RDN led to significant intimal thickening and significantly promoted the production of endothelin B receptor (ET B R) in vascular smooth muscle cells (VSMCs). Western blotting analysis indicated that RDN significantly suppressed the expression of AMPK/ Akt/eNOS signaling pathway proteins, and decreased the production of NO, and increased the expression of endothelin system proteins including endothelin-1 (ET-1), endothelin converting enzyme 1 (ECE1), endothelin A receptor (ET A R) and ET B R; and upregulated the expression of NOX2 and 4-HNE proteins and enhanced the activation of NF-kappa B (NF-κB) when compared with the sham treatment (all p < 0.05). There were no significant differences between the control and sham groups (all p > 0.05). Conclusions: RDN aggravated endothelial endocrine dysfunction and intimal thickening, and increased the risk of atherosclerosis in renal arteries of HFD-fed pigs.

Metformin Is Associated with the Inhibition of Renal Artery AT1R/ET-1/iNOS Axis in a Rat Model of Diabetic Nephropathy with Suppression of Inflammation and Oxidative Stress and Kidney Injury

“…In addition, ET-1 increases proteinuria, fibrosis and chronic kidney disease [ 36 ]. Our data demonstrate ET-1 upregulation and eNOS downregulation in renal artery tissues harvested from the model group of rats and appear consistent with a recent report showing a similar pattern of renal artery ET-1/eNOS expression obtained from obese pigs following renal denervation [ 37 ]. In addition, in vitro tissue bioassay using main branch human renal arteries demonstrated potent vasoconstriction induced by ET-1 with EC50 values of 4.06 nM [ 38 ].…”

Immediate Renal Denervation After Acute Myocardial Infarction Mitigates the Progression of Heart Failure via the Modulation of IL-33/ST2 Signaling

“…In our study, we observed reduced levels of sST2 after AMI by immediate RDN, together with changes in IL-33-related remodeling pathways, including reduced activation of NF-κb and expression of TGFβ. The inhibitory effect of RDN on NFκb has been demonstrated previously, which further supports our findings that RDN exerts anti-remodeling effects by the reduction of sST2 and the subsequent modulation of the IL-33/ST2 pathway (34,35).…”

Lipid Oxidation Products on Inflammation-Mediated Hypertension and Atherosclerosis: A Mini Review

“…However, this technique may cause endothelial injury and vascular dysfunction due to its invasiveness in nature. Su et al ( 38 ) assessed the risk of atherosclerosis induced by renal denervation in pigs fed with high-fat diet. Expression of 4-HNE was upregulated in addition to increased activation of NF-κB.…”