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.

Zuzana Honetschlägerová,Lucie Hejnová,Jiří Novotný,Aleš Marek,Luděk Červenka

doi:10.3390/biomedicines9121803

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).

Highlights

In the study employing the fawn-hooded hypertensive (FHH) rat, a unique genetic model of spontaneous hypertension associated with early development of chronic kidney disease (CKD), we found that Renal denervation (RDN) did not attenuate heart failure (HF)-dependent mortality and did not exhibit any essential renoprotective actions [16]
We found that RDN markedly attenuated HF-dependent mortality and substantially improved long-term survival in aorto-caval fistula (ACF) transgenic rats (TGR) [17]
The basal renal blood flow (RBF) was markedly lower in intact ACF TGR as compared with intact shamoperated TGR and RDN did not change the basal RBF, in sham-operated and ACF TGR (Figure 1B)

Summary

Introduction

Heart failure (HF) is a clinical syndrome which has become a major public health problem and the current treatment strategies fail to substantially attenuate the bleak prognosis, in patients in whom the disease is associated with the development of renal dysfunction (“cardiorenal syndrome”) and who were originally hypertensive [1,2,3]. New therapeutic approaches for the treatment of cardiorenal syndrome and HF are urgently needed and focused experimental studies are required to achieve this goal. Renal denervation (RDN) involving ablation of renal afferent and efferent nerve fibers was initially developed for the treatment of resistant hypertension and, despite some initial controversies, hypertension remains the main indication for RDN [4,5,6].

Objectives

Methods

Results

Discussion

Conclusion