Peripherally Administered Proinflammatory Cytokines Increase Afferent Renal Nerve Activity in Rat

Abstract

Inflammation plays an important role in sympathetic activation in cardiovascular diseases. Systemic administration of the proinflammatory cytokines (PICs) tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) increases mean blood pressure (MBP), heart rate (HR) and efferent renal sympathetic nerve activity. However, the renal nerve contains both afferent and efferent fibers. The afferent renal nerve is composed of chemoreceptor and mechanoreceptor fibers, and delivers peripheral signals to the brain that have been reported to increase sympathetic outflow in hypertension and heart failure. The effect of circulating PICs on afferent renal nerve activity (ARNA) has not previously been investigated. The present study sought to determine whether peripherally administered PICs TNF‐α and IL‐1β increase ARNA. Urethane anesthetized male Sprague Dawley rats (300–350 g) underwent an intravenous (IV) or a renal artery injection of TNF‐α or IL‐1β. MBP (mmHg), HR (beats/min) and ARNA (% change from baseline) were continuously recorded for 4–5 hours. IV injection of TNF‐α (500 ng/kg) or IL‐1β (500 ng/kg) significantly (* p<0.01 vs. baseline) increased MBP (20.1 ± 2.2* and 23.4 ± 2.1*, respectively), HR (51.5 ± 6.7* and 58.8 ± 7.1*, respectively) and ARNA (37.2 ± 3.5* and 42.1 ± 3.5*, respectively) with peak responses 20–30 mins after injection. Similarly, renal artery injection of the same doses of TNF‐α or IL‐1β induced increases (*p<0.01 vs. baseline) in MBP (17.0 ± 2.1* and 19.9 ± 2.2*, respectively), HR (45.5 ± 5.6* and 49.3 ± 4.6*, respectively) and ARNA (30.7 ± 3.5* and 38.4 ± 4.5*, respectively) that began within 5–10 mins and peaked at 20–30 mins after the injection. Quantitative real‐time PCR showed high mRNA levels of TNF‐α receptor 1 and IL‐1β receptor in renal cortex and medulla. These data indicate that circulating TNF‐α and IL‐1β can act at the kidney to augment afferent renal nerve activity, suggesting that circulating PICs may activate ARN fibers to elicit a sympathetically mediated pressor response. PIC activation of renal afferent nerves may be an important mechanism contributing to inflammation‐driven sympathetic activation in heart failure and hypertension. These findings provide support for the potential therapeutic benefit of renal afferent denervation.Support or Funding InformationSupported by NIH grant R01 HL139521 (S.G. Wei)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of intrarenal pelvic infusion of tumour necrosis factor-α and interleukin 1-β on reno-renal reflexes in anaesthetised rats

“…A major finding of the present study was the enhanced contralateral RSNA response to renal pelvic chemoreceptor stimulation by hypertonic NaCl in the presence of either TNF-α or IL-1β compared with vehicle (0.9% NaCl). These observations are consistent with the report that intravenous as well as intrarenal injection of TNF-α and IL-1β were found to activate (peaked at 20–30 min) afferent renal nerves and increase blood pressure and heart rate in anaesthetised rats [51]. The augmented renal sympatho-excitatory response to NaCl following elevated TNF-α levels could be a contributing factor in the maintenance and progression of hypertension due to a high-salt diet intake.…”

“…High renal levels of TNF-a and IL-1b have been reported in patients with end-stage renal disease and experimental models of kidney disease and hypertension [12,48,49]. TNFa and IL-1b receptors are both expressed in the kidney [50] with high levels of TNF-a (TNFR1) and IL-1b receptor mRNA found in the cortex and medulla [51]. There is increased renal expression of TNF-a and IL-1b receptors in response to inflammatory challenges, such as in glomerulonephritis and cisplatin-induced nephrotoxicity [50,52,53].…”