Effects of Renal Denervation on the Enhanced Renal Vascular Responsiveness to Angiotensin II in High-Output Heart Failure: Angiotensin II Receptor Binding Assessment and Functional Studies in Ren-2 Transgenic Hypertensive Rats

Abstract

Detailed mechanism(s) of the beneficial effects of renal denervation (RDN) on the course of heart failure (HF) remain unclear. The study aimed to evaluate renal vascular responsiveness to angiotensin II (ANG II) and to characterize ANG II type 1 (AT1) and type 2 (AT2) receptors in the kidney of Ren-2 transgenic rats (TGR), a model of ANG II-dependent hypertension. HF was induced by volume overload using aorto-caval fistula (ACF). The studies were performed two weeks after RDN (three weeks after the creation of ACF), i.e., when non-denervated ACF TGR enter the decompensation phase of HF whereas those after RDN are still in the compensation phase. We found that ACF TGR showed lower renal blood flow (RBF) and its exaggerated response to intrarenal ANG II (8 ng); RDN further augmented this responsiveness. We found that all ANG II receptors in the kidney cortex were of the AT1 subtype. ANG II receptor binding characteristics in the renal cortex did not significantly differ between experimental groups, hence AT1 alterations are not responsible for renal vascular hyperresponsiveness to ANG II in ACF TGR, denervated or not. In conclusion, maintained renal AT1 receptor binding combined with elevated ANG II levels and renal vascular hyperresponsiveness to ANG II in ACF TGR influence renal hemodynamics and tubular reabsorption and lead to renal dysfunction in the high-output HF model. Since RDN did not attenuate the RBF decrease and enhanced renal vascular responsiveness to ANG II, the beneficial actions of RDN on HF-related mortality are probably not dominantly mediated by renal mechanism(s).

Renal sympathetic denervation improves pressure-natriuresis relationship in cardiorenal syndrome: insight from studies with Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula

“…Even though our present study does not allow us to determine the exact mechanism(s) responsible for the improvement of the pressure-natriuresis relationship in ACF TGR after RDN, it is important to consider some important facts. First, our previous studies demonstrated that intrarenal concentration of norepinephrine (NE) is elevated in innervated ACF TGR, however, the state of intrarenal adrenergic receptors (determined as kidney mRNA and protein expression and also by receptor ligand binding studies) were not altered [39,71]. This indicated activation of RSNA in innervated ACF TGR because the rats exhibited increased NE concentration together with inappropriately maintained renal expression of adrenergic receptors.…”

The treatment with sGC stimulator improves survival of hypertensive rats with volume-overload induced heart failure and cardio-renal syndrome

“…Chronic HF due to volume overload was then induced by creating an aorto-caval stula (ACF) using a needle technique. This procedure is routinely performed in our laboratory and detailed description was reported repeatedly in our previous studies (Honetschlägerová et al 2021;Kala et al 2021Kala et al , 2023. Sham-operated rats underwent an identical procedure, but without creating ACF.…”

“…In the current work, we therefore, treated hypertensive, heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by creating an aorto-caval stula (ACF) with the sGC stimulator (BAY41-8543), which exhibits the same mode of action as riociguat and vericiguat (Sandner et al 2021b). ACF TGR model is a well-established model of volume-overload heart failure and it is routinely used in our laboratory for many years (Abassi et al 2011;Honetschlägerová et al 2021;Kala et al 2021Kala et al , 2023, because it represents a model of HF accompanied with development of cardio-renal syndrome. In addition, we also investigated an optimized dose of an ACE inhibitor (trandolapril) as the standard therapy for HF as positive control.…”

Renal Denervation Influences Angiotensin II Types 1 and 2 Receptors

“…One possibility that these authors initially stated was that the increase in vascular responsiveness induced by RDN depends on an increase in the density or affinity of AT1R and a decrease in the density or affinity of AT2R. However, they ultimately concluded that the exaggerated RBF response to Ang II could not simply be attributed to an increase in the number or affinity of AT1R before or after RDN [ 69 ]. In this regard, another study reported that there is no change in Ang II receptor binding affinity after subacute denervation, and an increase in vascular response was observed after denervation, indicating that renal denervation creates a stimulus to increase the number of Ang II receptors [ 4 ].…”

“…However, a study was also conducted by Zuzana Honetschlägerová and colleagues and showed that the effect of renal denervation on reducing HF mortality was unrelated to renal mechanisms. They showed that despite a significant decrease in blood pressure, renal denervation does not alter renal AT1R in mRen2 transgenic rats with HF [ 69 ].…”