Renal Denervation Normalizes Arterial Pressure With No Effect on Glucose Metabolism or Renal Inflammation in Obese Hypertensive Mice

Asirvatham‐Jeyaraj, Ninitha; Fiege, Jessica K.; Han, Renji; Foss, Jason D.; Banek, Christopher T.; Burbach, Brandon J.; Razzoli, Maria; Bartolomucci, Alessandro; Shimizu, Yoji; Panoskaltsis‐Mortari, Angela; Osborn, John W.

doi:10.1161/hypertensionaha.116.07993

Cited by 20 publications

(18 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These variations, in addition to different routes of administration of glucose, could have led to inconsistent results and conclusions between our present study and that by Asirvatham-Jeyaraj et al. [61] .…”

Section: Discussioncontrasting

confidence: 87%

“…In contrast, a recent study reported that renal denervation does not improve glucose tolerance in obese hypertensive mice [61] . It is very likely that the authors of that report did not see any improvement in glucose tolerance because the mice were administered glucose based on their body weight.…”

Section: Discussionmentioning

confidence: 85%

“…Hence, the obese mice received a higher glucose dose compared to lean mice, which might have affected their response to glucose tolerance tests. Moreover, the mice in that study [61] were fasted for 14 h prior to glucose tolerance tests, which is different than our protocol of fasting the mice for only 6 h [30] . These variations, in addition to different routes of administration of glucose, could have led to inconsistent results and conclusions between our present study and that by Asirvatham-Jeyaraj et al.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Chhabra

Morgan

Tooke

et al. 2017

Molecular Metabolism

View full text Add to dashboard Cite

ObjectiveHypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc−/−) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc−/− mice could explain their elevated glycosuria and consequent enhanced glucose tolerance.MethodsWe measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc−/− mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc−/− mice or the renal-denervated mice.ResultsConsistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc−/− mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc−/−, WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc−/− mice.ConclusionHence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.

show abstract

Section: Discussioncontrasting

confidence: 87%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Chhabra

Morgan

Tooke

et al. 2017

Molecular Metabolism

View full text Add to dashboard Cite

show abstract

“…Given the presence of sympathetic activation in obesity and its possible role in pathogenesis of obesity-associated hypertension, as described above, it may be expected that sympathetic inhibition might have a relevant impact in obese patients. Indeed, renal denervation seems able to restore insulin sensitivity in obese dogs (Iyer et al, 2016 ) but not in obese hypertensive mice (Asirvatham-Jeyaraj et al, 2016 ). Bilateral renal denervation greatly attenuated sodium retention and hypertension in obese dogs fed a high-fat diet (Kassab et al, 1995 ).…”

Section: The Ans As a Therapeutic Target In Obesitymentioning

confidence: 99%

The Role of the Autonomic Nervous System in the Pathophysiology of Obesity

et al. 2017

View full text Add to dashboard Cite

Obesity is reaching epidemic proportions globally and represents a major cause of comorbidities, mostly related to cardiovascular disease. The autonomic nervous system (ANS) dysfunction has a two-way relationship with obesity. Indeed, alterations of the ANS might be involved in the pathogenesis of obesity, acting on different pathways. On the other hand, the excess weight induces ANS dysfunction, which may be involved in the haemodynamic and metabolic alterations that increase the cardiovascular risk of obese individuals, i.e., hypertension, insulin resistance and dyslipidemia. This article will review current evidence about the role of the ANS in short-term and long-term regulation of energy homeostasis. Furthermore, an increased sympathetic activity has been demonstrated in obese patients, particularly in the muscle vasculature and in the kidneys, possibily contributing to increased cardiovascular risk. Selective leptin resistance, obstructive sleep apnea syndrome, hyperinsulinemia and low ghrelin levels are possible mechanisms underlying sympathetic activation in obesity. Weight loss is able to reverse metabolic and autonomic alterations associated with obesity. Given the crucial role of autonomic dysfunction in the pathophysiology of obesity and its cardiovascular complications, vagal nerve modulation and sympathetic inhibition may serve as therapeutic targets in this condition.

show abstract

“…This may be expressed initially as increased infiltration of T cells leading to the generation of cytokines, for example TNF‐α, and thereafter the production of pro‐inflammatory mediators such as bradykinin. This was explored further in a recent report in mice which showed that following 10 weeks of a high‐fat diet, there was hypertension, hyperglycaemia and increased inflammatory markers in the kidney. Although renal denervation normalized blood pressure, the markers of renal inflammation persisted.…”

Section: The Renal Afferent Nerves In Pathophysiological Statesmentioning

confidence: 99%

The innervation of the kidney in renal injury and inflammation: a cause and consequence of deranged cardiovascular control

Abdulla

Johns

2017

Acta Physiologica

View full text Add to dashboard Cite

Extensive investigations have revealed that renal sympathetic nerves regulate renin secretion, tubular fluid reabsorption and renal haemodynamics which can impact on cardiovascular homoeostasis normally and in pathophysiological states. The significance of the renal afferent innervation and its role in determining the autonomic control of the cardiovascular system is uncertain. The transduction pathways at the renal afferent nerves have been shown to require pro-inflammatory mediators and TRPV1 channels. Reno-renal reflexes have been described, both inhibitory and excitatory, demonstrating that a neural link exists between kidneys and may determine the distribution of excretory and haemodynamic function between the two kidneys. The impact of renal afferent nerve activity on basal and reflex regulation of global sympathetic drive remains opaque. There is clinical and experimental evidence that in states of chronic kidney disease and renal injury, there is infiltration of T-helper cells with a sympatho-excitation and blunting of the high- and low-pressure baroreceptor reflexes regulating renal sympathetic nerve activity. The baroreceptor deficits are renal nerve-dependent as the dysregulation can be relieved by renal denervation. There is also experimental evidence that in obese states, there is a sympatho-excitation and disrupted baroreflex regulation of renal sympathetic nerve activity which is mediated by the renal innervation. This body of information provides an important basis for directing greater attention to the role of renal injury/inflammation causing an inappropriate activation of the renal afferent nerves as an important initiator of aberrant autonomic cardiovascular control.

show abstract

Renal Denervation Normalizes Arterial Pressure With No Effect on Glucose Metabolism or Renal Inflammation in Obese Hypertensive Mice

Cited by 20 publications

References 38 publications

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

The Role of the Autonomic Nervous System in the Pathophysiology of Obesity

The innervation of the kidney in renal injury and inflammation: a cause and consequence of deranged cardiovascular control

Contact Info

Product

Resources

About