Abstract
Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1–4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension.
Highlights
After high hopes were raised with respect to the potential of renal denervation in the treatment of arterial hypertension [29], the sobering results of the Simplicity 3 Trial in 2015 [5] questioned the future of this innovative procedure in the treatment of high blood pressure (BP)
Data of ours suggested that inflammation and fibrosis influence afferent nerve pathways of the kidney [9, 41]. These findings made us test the hypothesis that in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]), the excitability of afferent renal pathways is increased as assessed by the gain of tonic, potentially highly active neurons in respective neuronal cell culture samples dependent on the degree of renal inflammation and fibrosis in the respective animals
Mean arterial BP was significantly higher in 2K1C than in controls, whereas body weight was significantly lower and heart rate was comparable between both groups (Table 1)
Summary
After high hopes were raised with respect to the potential of renal denervation in the treatment of arterial hypertension [29], the sobering results of the Simplicity 3 Trial in 2015 [5] questioned the future of this innovative procedure in the treatment of high blood pressure (BP). New and carefully designed studies with specific questions in well-controlled cohorts [1, 14, 47] suggest far smaller BP effects of renal denervation than originally assumed, that maybe of therapeutic significance for the treatment of resistant hypertension [37] Regardless of these new developments in the field of renal nerve ablation, it is still controversial how renal innervation influences systemic autonomous nerve activity [37]. In patients with end-stage renal disease and/ or hypertension that have undergone bilateral nephrectomy [6, 19], normalization of formerly increased sympathetic activity as assessed by recordings of peripheral sympathetic nerve fibers strongly suggests an important role of renal sensory afferent innervation in the regulation of efferent sympathetic tone. These clinical observations did not answer the question of how afferent renal nerve pathways will influence sympathetic activity in hypertension
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