Angiotensin Receptor Blockade to Treat Tacrolimus‐Associated Hypertension: Is There a Benefit Beyond Blood Pressure Reduction?

In a recent issue of Acta Physiologica, Fei and colleagues re-visit the question of whether angiotensin receptor blockers (ARBs) might protect against hypertension-mediated organ damage through a ‘super-added’ mechanism: that is, through pathways operating independently from blood pressure reduction 1. This concept enjoyed some popularity in the early 2000s, after prominent clinical trials suggested that renin-angiotensin system (RAS) inhibitors conferred benefits that were disproportionate to that expected from their anti-hypertensive effect alone 2, 3. The prevailing wisdom was that RAS blockade might directly improve cardiac and vascular remodeling, given that AngII signaling drives pro-proliferative, pro-inflammatory, pro-fibrotic pathways in the myocardium and arteries. Many randomized controlled trials have since shown that, in unselected hypertensive populations, RAS inhibitors are no different from thiazide diuretics or calcium channel blockers in their ability to prevent hypertension-mediated organ damage (HMOD) 4, 5. The corollary is that the therapeutic effect of these drug classes must be mediated directly through their ability to lower blood pressure. However, given the very different ways in which these agents perturb cardiovascular physiology, it is nevertheless plausible that classes of anti-hypertensive might differ in their efficacy at preventing HMOD in some contexts. In the context of tacrolimus-induced hypertension, Fei et al. 1 hypothesize that the ARB valsartan protects against vascular senescence. In complementary histological, molecular and functional analyses, they dissect the phenotype of tacrolimus-induced hypertension in the mouse and test the therapeutic properties of valsartan and the senolytic Bcl-2 inhibitor, ABT-263. This is a lovely example of using multi-modal assays to give a holistic understanding of systemic physiology. In particular, the authors should be lauded for studying vascular reactivity in renal afferent arterioles: a vascular bed that is crucial for systemic blood pressure/fluid homeostasis but often neglected by experimentalists in favor of more tractable systems. They show that tacrolimus causes RAS activation, vascular remodeling with impaired vasorelaxation in resistance arteries and upregulation of senescence markers in vascular endothelial and smooth muscle cells: phenomena that were all reversed by valsartan. Those observations are compatible with our prior understanding of tacrolimus-induced hypertension (Figure 1, gray arrows). Calcineurin inhibitors (CNIs) are known to activate the RAS, alongside their other pro-hypertensive effects (endothelin signaling, sympathetic nervous system activation, stimulation of the thiazide-sensitive sodium chloride co-transporter, NCC) 6. Both RAS activation and hypertension per se are known to accelerate vascular cell senescence 7, 8. However, the work by Fei et al. raises some intriguing questions about other mechanisms that may be at play (Figure 1, red arrows). This first question is the extent to which ARBs mediate a direct anti-senescent effect that is additional to that caused by a drop in blood pressure (Figure 1, h1). In cultured vascular cells, tacrolimus upregulated the senescence marker SA-β-galactosidase and valsartan blocked this. In this ex vivo system, that is compatible with effects mediated by a cell-intrinsic RAS, although the underlying mechanism was not delineated in detail. The critical question is whether this cellular phenomenon exerts any meaningful effect on in vivo cardiovascular physiology. Importantly, Fei et al. included a control group of mice treated with an alternative anti-hypertensive: amlodipine. Amlodipine treatment reduced expression of senescence markers in vascular tissue, supporting the null hypothesis that changes in senescence are mediated primarily by changes in blood pressure, rather than any direct effect of tacrolimus or valsartan on vascular cells. However, the authors argue that evidence for such a direct effect might lie in the observation that amlodipine exerted a blood pressure drop of a similar magnitude to valsartan but had a lesser effect on senescence markers. This is intriguing, but this single mouse study in which blood pressure was assessed by a single measure at 28 days in the amlodipine group clearly needs replication. Understanding which vascular cell types are involved, and the mechanism of any knock-on effects on vessel physiology will be important. The second question is whether senolytic therapies could have a place in preventing hypertension-mediated organ damage (Figure 1, h2). Perhaps the most intriguing observation made by Fei et al. was that ABT-263 therapy prevented tacrolimus-induced hypertension and restored vasoreactivity in resistance vessels. The time course—with effects noted within the first week of therapy—is hard to reconcile with a mechanism dependent on vascular remodeling. There are tantalizing open questions. Was the anti-hypertensive effect due to senolytic activity in vascular cells? Are all vascular beds affected equally? Is this a generic property of senolytic therapy or a specific effect of ABT-263? This adds to the mystique of senolytic therapy, which has been shown in murine models to extend lifespan through pleiotropic mechanisms 9. This paper raises fascinating questions that will prompt further mechanistic research, with potentially broad clinical implications. ‘Chronic allograft nephropathy’ (or ‘interstitial fibrosis/tubular atrophy’) is a leading cause of kidney transplant failure, and senescence is increasingly recognized as an important contributor/potential therapeutic target 10. Perhaps RAS blockade will turn out to be a simple method of targeting that process in the vascular compartment. More broadly, if we think of CNI-induced senescence as iatrogenic accelerated vascular aging, we may be able to extend observations from this context to develop better treatments for age-related hypertensive and vascular disease in the general population. The author has nothing to report. The author declares no conflicts of interest. The author has nothing to report.