Obesity gets on your renal nerves

In the present issue of Acta Physiologica,1 Khan et al. in their article ‘Improvement in baroreflex control of renal sympathetic nerve activity in obese Sprague-Dawley rats following immunosuppression’ confirm that obesity-related hypertension involves resetting of the arterial baroreceptor to a state of less sensitivity and relate this mechanistically to inflammation-induced altered renal afferent nerve activity.1 Pharmacological treatment with the calcineurin phosphatase inhibitor-type immunosuppressant tacrolimus attenuated inflammation, reversed, paradoxically, the hypertension and restored baroreceptor sensitivity similar to the effect of renal denervation. The paper not only points attention towards a mechanistic understanding of the baroreceptor resetting associated with chronic arterial hypertension but also demonstrates a pharmacological approach to remedy obesity-associated hypertension. Arterial hypertension remains a major global health problem and with overweight and overt obesity being similar large burdens for individuals and healthcare systems. Obesity increases the incidence of hypertension. Normally, the arterial baroreceptors detect acute changes in blood pressure through altered vascular wall stretch and buffer large fluctuations in pressure through counter regulatory changes in efferent sympathetic nerve activity. Sympathetic nerves control resistance vessel tone/peripheral vascular resistance, venous compliance, cardiac function and adrenal medulla release of adrenaline. It has been known for decades that baroreceptors are dysfunctional in human hypertension and fail to protect against chronically elevated pressure.2 A threshold for activity in afferent sensory neurones requiring higher pressure and a lower firing activity is characteristic for dysfunction – at least in rat hypertension models.3 The baroreceptor should be regarded as a modifiable pathogenic factor as exogenous electrical field stimulation of the afferent nerves by cuffs placed around carotid artery, ‘barostim’, will simulate an increased pressure and diminish sympathetic efferent nerve traffic. The method has proven efficient in human hypertension where baroreceptor stimulation resulted in significant and large drops in pressure and heart rate associated with lower plasma renin and skeletal muscle sympathetic nerve traffic.4 It has been a scientific challenge to unravel the underlying mechanisms by which the arterial baroreceptors adapt to elevated pressure. Khan et al. studied an obesity-induced experimental model of hypertension in rats. In humans, obesity-related hypertension displays impaired baroreflex cardiovascular control.5 Obesity-related hypertension can be efficiently offset in experimental models by baroreceptor stimulation.6 Why focus on the kidneys as the origin for impaired baroreceptor control in obesity-induced hypertension? First, the kidneys are important in long-term control of arterial blood pressure. The baroreceptor influences renal excretion of sodium6 and renin release.6 A previous study by the Khan group showed that renal denervation, the physical interruption of nerves to and from the kidney, normalized baroreceptor sensitivity. In the present study of Khan et al.,7 authors hypothesized a role for renal afferent nerves in the adverse resetting of baroreceptor activity and it was a logical follow-up on a previous study from Acta Physiologica. In both studies, rats were subjected to 6–8 weeks of excess fat feeding which led to significantly more weight gain, hypertension, increased glomerular filtration rate and attenuated fractional excretion of Na+. In both studies, there were impaired arterial baroreceptor gain curves for renal sympathetic nerve activity and heart rate that were re-established by bilateral renal denervation suggesting that renal nerves affect the setpoint of the baroreceptor in obesity.1, 7 Previous studies of Campese et al.8 discriminated between afferent and efferent renal nerve activity in a different renal injury hypertension model where dorsal rhizotomy, with deletion of afferent nerves only, resulted in blood pressure decline. However, this approach was not undertaken in the present study and a direct extrapolation is not possible due to different experimental models.1, 7, 8 In both studies, a potential contribution of altered function in the low-pressure baroreceptor reflex was examined using saline infusion to expand extracellular volume. Volume expansion would be predicted to lower sympathetic efferent renal nerve activity and heart rate similarly to an abrupt increase in blood pressure. The data showed an impaired baroreflex response also in low-pressure area in obesity-induced hypertension, and marked improvement in the response by bilateral renal denervation1, 7 Thus, the high fat diet-induced baroreflex impairment was similarly dysfunctional in low- and high-pressure vascular areas. The mechanism was not clarified by Khan et al.7 in the 2015 paper beyond that it depended on renal nerves. The present study takes these previous findings one step further by showing increased plasma and renal tissue level of inflammatory biomarkers in obesity-related hypertension that were suppressed by tacrolimus but not by denervation. The essential new finding was that immunosuppression by tacrolimus attenuated hypertension and arterial baroreflex impairment similar to, but not additive with, renal denervation after high fat feeding in agreement with but not proving a common pathway.1 Of note, tacrolimus did not affect baroreflex setting in normotensive control rats and also did not alter baseline blood pressure. Calcineurin phosphatase inhibitors are known as a class effect to induce hypertension by stimulating renin-angiotensin system activity and to induce endothelial dysfunction. On the other hand, data are accumulating, which show a clear inflammatory component in the pathogenesis of hypertension. Obviously, in a complex in vivo model, some questions remain open for interpretation. Authors discuss the possibility that ANGII and aldosterone could mediate most of the obesity-related manifestations and at least aldosterone also promotes inflammation. ANGII and aldosterone were not measured. Inflammation was likely not restricted to the kidney, but renal nerve traffic and renal noradrenaline spillover were increased by fat feeding. Infiltrating bone marrow-derived cell, for example macrophages and T cells, were not mapped in the renal (or other) interstitia. Both cell types produce interleukins known to promote hypertension. It would be interesting to delineate what tacrolimus did to renal and vascular infiltrating cells and to explore whether administration of cytokines could mimic the adiposity-induced phenotype. Moreover, although impaired urinary sodium excretion and decreased Na+/K+ ratio was documented, no information was provided as to concurrent changes in renal Na+ transport protein abundance and/or localization. Another question not addressed was the degree of metabolic disturbance in the rats and whether impaired glucose tolerance or overt type-2 diabetes with altered insulin and microalbuminuria was present and might have confounded results. A point of discussion is indeed whether it can be safely concluded that renal afferent nerve traffic is the dominant factor. Denervation is likely to suppress renin and thereby ANGII and aldosterone, which will promote Na+ excretion. The high fat intake-induced hypertension was impaired by denervation. However, the study demonstrates that adiposity and inflammation in rats were associated with hypertension, dysfunctional baroreflex and increased sympathetic traffic engaging the kidneys. This interaction was effectively interrupted by an immunosuppressive drug known to act preferentially on T cells. The study confirms a role for inflammation in adiposity-associated hypertension. The author declares no conflict of interests.