Cassia Toledo Bergamaschi

Afferent nerves from the renal pelvis contribute to the modulation of renal sympathetic nerve activity (rSNA) in response to low-dose furosemide intravenous administration. Capsaicin-sensitive C-fiber afferents, located in the renal pelvis, selectively alter the pattern of sympathetic outflow to the kidneys. Intrapelvic low-dose furosemide increases rSNA without affecting splanchnic sympathetic nerve activity (sSNA).

Key Points: Systemic arterial hypertension is a frequent early onset manifestation in autosomal dominant polycystic kidney disease (ADPKD) contributing to progression. Assessment of cardiovascular autonomic function in young patients with ADPKD before hypertension or renal decline revealed no abnormalities. Findings showed no autonomic dysfunction, but high urinary angiotensinogen suggests early intrarenal renin angiotensin-aldosterone system activation in normotensive patients with ADPKD. Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease, leading to progressive renal function loss. Systemic arterial hypertension is a frequent early-onset extrarenal manifestation with an incompletely understood pathogenesis. Therefore, this study investigated cardiovascular autonomic control at rest and during physiological sympathetic stimulation, along with humoral and urinary molecules involved in BP regulation, in young patients with ADPKD before hypertension and renal dysfunction onset. Methods: Eighteen normotensive patients with ADPKD (11 female/7 male, 27.7±6.4 years) and 19 age- and sex-matched healthy controls (9 female/10 male, 25.7±3.8 years) participated in this study. Based on Mayo Clinic imaging criteria, patients with ADPKD were classified as rapid or slow progressors. Heart rate variability, BP variability, and spontaneous baroreflex sensitivity (BRS) were assessed at rest, with BRS further evaluated during the Valsalva maneuver. Cardiovascular reactivity to sympathoexcitation was examined using the cold pressor test, Stroop test, and static handgrip exercise. Neuropeptide Y, angiotensinogen (AGT), and inflammatory and endothelial function markers were measured in blood, whereas monocyte chemoattractant protein-1, AGT, and albumin were analyzed in urine. Results: Heart rate variability, BP variability, BRS, and cardiovascular reactivity did not differ between patients and controls or between rapid and slow progressors. Serum markers and urinary monocyte chemoattractant protein-1 were also not different between groups. However, urinary AGT and albumin levels were significantly higher in patients. Conclusions: These findings suggest that cardiovascular autonomic dysregulation, systemic inflammation, and endothelial dysfunction are absent in early-stage ADPKD, whereas intrarenal renin-angiotensin-aldosterone system is overactivated and potentially plays a key role in triggering hypertension.

The Goldblatt model of hypertension (2K-1C) in rats is characterized by renal sympathetic nerve activity (rSNA). We investigated the effects of unilateral renal denervation of the clipped kidney (DNX) on sodium transporters of the unclipped kidneys and the cardiovascular, autonomic, and renal functions in 2K-1C and control (CTR) rats. The mean arterial pressure (MAP) and rSNA were evaluated in experimental groups. Kidney function and NHE3, NCC, ENaCβ, and ENaCγ protein expressions were assessed. The glomerular filtration rate (GRF) and renal plasma flow were not changed by DNX, but the urinary (CTR: 0.0042 ± 0.001; 2K-1C: 0.014 ± 0.003; DNX: 0.005 ± 0.0013 mL/min/g renal tissue) and filtration fractions (CTR: 0.29 ± 0.02; 2K-1C: 0.51 ± 0.06; DNX: 0.28 ± 0.04 mL/min/g renal tissue) were normalized. The Na⁺/H⁺ exchanger (NHE3) was reduced in 2K-1C, and DNX normalized NHE3 (CTR: 100 ± 6; 2K-1C: 44 ± 14, DNX: 84 ± 13%). Conversely, the Na⁺/Cl⁻ cotransporter (NCC) was increased in 2K-1C and was reduced by DNX (CTR: 94 ± 6; 2K-1C: 144 ± 8; DNX: 60 ± 15%). In conclusion, DNX in Goldblatt rats reduced blood pressure and proteinuria independently of GRF with a distinct regulation of NHE3 and NCC in unclipped kidneys.

La litiasis renal (LR) es una enfermedad de alta prevalencia mundial. Los estudios indican que existe una correlación entre la presencia de LR y el desarrollo de enfermedades cardiovasculares. Investigar el posible papel del sistema nervioso autónomo (SNA) en el riesgo cardiovascular (RCV) de pacientes con LR. Se incluyeron 19 pacientes diagnosticados de LR y 21 individuos sin LR en el grupo control (CTL). Se evaluaron las presiones arteriales sistólica (PAS), diastólica (PAD) y media (PAM), frecuencia cardíaca (FC) en reposo y en respuesta a desafíos cardiovasculares, como ortostatismo y prueba de Stroop. Se realizaron análisis bioquímicos en sangre y orina 24 horas, de todos los participantes del estudio, reclutamiento en la consulta externa de nefrología/ litiasis renal en el periodo de 2017-2019. El grupo LR presentó mayores niveles de colesterol LDL (102,9±24,0 vs 92,4±33,0 mg/dL, p=0,02), glicemia (87,5±8,5 vs 80,3±7,3 mg/dL, p=0,003) y volumen urinario (1966±789 vs 1600±574 mL, p=0,006). El grupo con LR presentó valores más altos de PAS y PAD durante el ortostatismo en comparación con el grupo CTL (PAS: 126±15 vs 122±9 mmHg, p<0,05 y PAD: 81±8 vs 79±7 mmHg, p<0,05, LR vs CTL, respectivamente). En la prueba de Stroop, en el análisis de los deltas absolutos de PAS (9±10 vs 2±8 mmHg, p<0,05) y FR (13±7 vs 8±7 lpm, p<0,05), el grupo LR presentó valores más altos. Se encontró evidencia de posibles alteraciones autonómicas en respuesta al ortostatismo y a la prueba de Stroop, que podrían estar relacionadas con el papel del SNA en el CVR de pacientes con LR. Palabras clave: litiasis renal, barorreflejo, estrés fisiológico, presión arterial, riesgo cardiovascular, sistema nervioso autónomo.

The impact of obesity upon bone metabolism is controversial since both beneficial or harmful effects have been reported. Bone remodeling is modulated by the central nervous system through cytokines, hormones and neuromodulators. The present study aimed to evaluate the effects evoked by bilateral retroperitoneal white adipose tissue (rWAT) denervation (Dnx) upon bone mineral metabolism and remodeling in an experimental model of obesity in rats. Male Wistar rats were fed during 18 weeks with high-fat diet (HFD) or standard diet (SD) as controls, and rWAT Dnx or Sham surgery was performed at the 14th week. Biochemical and hormonal parameters, bone histomorphometry, rWAT and hypothalamus protein and gene expression were analyzed. The HFD group presented decreased bone formation parameters, increased serum and bone leptin and FGF23, increased serum and hypothalamic neuropeptide Y (NPY) and decreased serum 1,25-dihydroxyvitamin D₃ and PTH. After rWAT Dnx, bone markers and histomorphometry showed restoration of bone formation, and serum and hypothalamic NPY decreased, without alteration in leptin levels. The present study shows that the denervation of rWAT improved bone formation in obese rats mediated by a preferential reduction in neurohormonal actions of NPY, emphasizing the relevance of the adipose tissue–brain–bone axis in the control of bone metabolism in obesity.

The impact of obesity upon bone metabolism is controversial since both negative and positive effects have been reported. Bone remodeling is modulated by the central nervous system through cytokines, hormones and neuromodulators. The present study aimed to evaluate the effects evoked by bilateral retroperitoneal white adipose tissue (rWAT) denervation (Dnx) upon bone mineral metabolism and remodeling in an experimental model of obesity in rats. Male Wistar rats were fed during 18 weeks with high-fat diet (HFD) or standard diet (SD) as controls, and rWAT Dnx or Sham surgery was performed at the 14th week. Biochemical and hormonal parameters, bone histo-morphometry, rWAT and hypothalamus protein and gene expression were analyzed. HFD group presented decreased bone formation parameters, increased serum and bone leptin and FGF23, increased serum and hypothalamic neuropeptide Y (NPY) and decreased serum 1,25-dihydroxyvitamin D3 and PTH. After rWAT Dnx, bone markers and histomorphometry showed restoration of bone formation, serum and hypothalamic NPY decreased, without altera-tion in leptin levels. The present study showed that the denervation of rWAT improved bone formation in obese rats mediated by a preferential reduction in neurohormonal actions of NPY, emphasizing the relevance of the adipose tissue-brain-bone axis in the control of bone metabolism in obesity.

We examined the effects of an acute increase in blood pressure (BP) and renal sympathetic nerve activity (rSNA) induced by bicuculline (Bic) injection in the paraventricular nucleus of hypothalamus (PVN) or the effects of a selective increase in rSNA induced by renal nerve stimulation (RNS) on the renal excretion of sodium and water and its effect on sodium-hydrogen exchanger 3 (NHE3) activity. Uninephrectomized anesthetized male Wistar rats were divided into three groups: (1) Sham; (2) Bic PVN: (3) RNS + Bic injection into the PVN. BP and rSNA were recorded, and urine was collected prior and after the interventions in all groups. RNS decreased sodium (58%) and water excretion (53%) independently of BP changes (p < 0.05). However, after Bic injection in the PVN during RNS stimulation, the BP and rSNA increased by 30% and 60% (p < 0.05), respectively, diuresis (5-fold) and natriuresis (2.3-fold) were increased (p < 0.05), and NHE3 activity was significantly reduced, independently of glomerular filtration rate changes. Thus, an acute increase in the BP overcomes RNS, leading to diuresis, natriuresis, and NHE3 activity inhibition.

This study aimed to verify the effects of an acute increase in blood pressure (BP) and/or renal sympathetic nerve activity (rSNA) on the renal excretion of sodium and water and its potential effect on the regulation of NHE3 activity. Uninephectomized anesthetized male Wistar rats were divided into three experimental groups: 1) Sham, the rats had their BP and rSNA recorded, and urine was collected for 2 h; 2) bicuculline (Bic) paraventricular nucleus of the hypothalamus (PVN), rat BP, and rSNA were recorded, and urine was collected for 1 h at baseline conditions and 1 h after bicuculline injection into the PVN; 3) RNS + Bicuculine injection into the PVN, BP, and rSNA were recorded, and urine was collected 1h after RNS and 1 h after bicuculline injection into the PVN. Renal nerve stimulation (RNS) decreased sodium and water excretion independent of changes in BP. However, after Bic in the PVN during RNS stimulation, BP and rSNA increased up to 30% and 60%, respectively, increasing diuresis (5-fold) and natriuresis (2.3-fold), accompanied by a significant reduction in the NHE3 activity independent of GFR changes. In conclusion, an acute increase in BP overcomes such effects, generating diuresis, natriuresis, and NHE3 activity inhibition.

Sepsis causes long-term disability, such as immune dysfunction, neuropsychological disorders, persistent inflammation, catabolism, and immunosuppression, leading to a high risk of death in survivors, although the contributing factors of mortality are unknown. The purpose of this experimental study in rats was to examine renal (rSNA) and splanchnic (sSNA) sympathetic nerve activity, as well as baroreflex sensitivity, in acute and chronic post-sepsis periods. The rats were divided into two groups: control group with naïve Wistar rats and sepsis group with 2-mL intravenous inoculation of Escherichia coli at 10⁸ CFU/mL. Basal mean arterial pressure, heart rate, rSNA, sSNA, and baroreflex sensitivity were evaluated in all groups at the acute (6 h) and chronic periods (1 and 3 months). Basal rSNA and sSNA were significantly reduced in the surviving rats, as was their baroreflex sensitivity, for both pressor and hypotensive responses, and this effect lasted for up to 3 months. A single episode of sepsis in rats was enough to induce long-term alterations in renal and splanchnic sympathetic vasomotor nerve activity, representing a possible systemic event that needs to be elucidated. These findings showed that post-sepsis impairment of sympathetic vasomotor response may be one of the critical components in the inability of sepsis survivors to respond effectively to new etiological illness factors, thereby increasing their risk of post-sepsis morbidity.