Sympathetic activation plays a role in heart failure (HF) development. Afferent renal nerve input may induce sympathoexcitation via the hypothalamic paraventricular nucleus (PVN), which projects to the rostral ventrolateral medulla, a center for sympathetic regulation. Central dendritic release of vasopressin from PVN neurons reportedly stimulates neighboring presympathetic neurons, causing sympathoexcitation. This study investigated whether afferent renal nerves contribute to hypertensive cardiac dysfunction and whether the afferent renal nerve-PVN axis mediates sympathoexcitation via central vasopressin using salt-loaded Dahl salt-sensitive rats, a model of hypertensive HF. Salt loading began at 6 weeks of age, with selective afferent renal denervation and total renal denervation performed at 9 weeks in Dahl salt-sensitive rats. HF phenotypes were examined at 16 weeks, while sympathomodulation by afferent renal denervation was assessed at 12 weeks, the pre-HF phase. At 16 weeks, afferent renal denervation and total renal denervation similarly improved left ventricular systolic dysfunction, reduced myocardial fibrosis and related mRNA levels, and lowered plasma norepinephrine levels without reducing blood pressure in hypertensive rats. At 12 weeks, afferent renal denervation attenuated the increase in plasma norepinephrine and presympathetic neuron activity in the PVN and rostral ventrolateral medulla in hypertensive rats, while decreasing vasopressin-producing PVN neuron activity. In acute experiments, afferent renal nerve stimulation increased sympathetic outflow, but vasopressin V1a and V1b receptor blockade in the PVN suppressed this sympathoexcitation in hypertensive rats. Afferent renal nerve input activates the sympathetic nervous system before left ventricular systolic dysfunction and contributes to hypertensive HF, with PVN vasopressin driving this sympathoexcitation.

Controversy exists on which metabolites determine the exaggerated exercise pressor reflex (EPR) in peripheral artery disease (PAD). In decerebrated rats, we investigated the role played by lactate and hydrogen ions in a model of PAD, which was simulated by ligating the femoral artery for 72 h before the start of the experiment. Production of lactate and hydrogen ions by the contracting hindlimb muscles was manipulated by knocking out the myophosphorylase gene (pygm). In both knockout (pygm-/-; n = 13; 6-females) and wild-type rats (pygm+/+; n = 14; 7-females), the EPR was evoked by statically contracting the triceps-surae muscles. Blood pressure, tension, and renal sympathetic nerve activity were measured. Responsiveness of the metabolic component of the EPR was evaluated by intra-arterial injections of lactic acid and diprotonated phosphate solutions. Responsiveness of the mechanical component of the EPR was evaluated by stretching the calcaneal tendon. In each rat, the pressor responses evoked from the freely perfused triceps-surae muscles were compared to those evoked from the contralateral ischemic triceps-surae muscles. In pygm+/+ rats whose femoral artery was ligated, static contraction, lactic-acid injection and diprotonated phosphate injection evoked pressor responses that were 88%, 22%, and 58% greater than those evoked from muscles whose femoral arteries were freely perfused. In pygm-/- rats, ligation of the femoral artery for 72 h had no effect. In both groups, 72 h of femoral artery ligation exacerbated the pressor response to passive stretch. Lactate and hydrogen-ions accumulation in contracting myocytes plays a key role in exaggerating the metabolic component of the EPR evoked from hindlimb muscles with chronically-ligated femoral arteries.

FDA approval for catheter-based renal nerve ablation has sparked renewed interest in the role of renal nerves in hypertension and their potential contribution to other pathophysiologies. While the anti-hypertensive effects of catheter-based renal nerve ablation were thought to be due to the ablation of the sympathetic efferent nerves going to the kidney, preclinical hypertensive rodent studies and unexpected beneficial clinical outcomes have highlighted the renal afferent (sensory) nerves as a contributor to the pathogenesis of hypertension. Renal afferents are most abundant in the renal pelvis but also innervate the renal cortex. Their neurochemical and functional diversity remains to be fully elucidated. Tracing studies from the kidney to the central nervous system (CNS) have identified direct projections of spinal afferents with cell bodies in dorsal root ganglia to both the spinal cord and caudal brainstem. Few studies have suggested vagal innervation of the kidney with cell bodies in the nodose ganglia. The central processing of renal afferent input in brain autonomic circuits is not thoroughly understood. Regions involved in renal afferent input processing include the paraventricular nucleus of the hypothalamus and nucleus of the solitary tract which integrate peripheral sensory inputs with central homeostatic sensing regions including circumventricular organs. This review aims to summarize our current understanding of renal afferent anatomy including tracing and immunolabeling studies from the kidney to the CNS, the general mechanosensitive and chemosensitive subtypes in the kidney, and broadly discuss a potential pathway for the central processing of renal afferent input through autonomic and other homeostatic nuclei.

Altered gut microbiota composition has been implicated in the development of hypertension. Evidence suggests bacterial products and metabolites can enter circulation, act on peripheral tissues, and modulate blood pressure (BP). We identified extracellular vesicles (EVs) of bacterial origin (bacterial extracellular vesicles [bEVs]) in the circulation of spontaneously hypertensive stroke-prone rats (SHRSP). We hypothesized that bEVs mediate communication between microbiota and the host, and that bEVs from SHRSP microbiota contain unique cargo that promotes hypertension. EVs were isolated from plasma and cecal content of SHRSP and Wistar-Kyoto (WKY) rats. Multiomics analysis, including 16S rRNA sequencing, small RNA sequencing, lipidomics, and proteomics were performed to assess the cargo of bEVs. BEVs from WKY and SHRSP were transplanted by oral gavage to WKY and SHRSP recipients, and the effects on BP and sympathetic activity were monitored. The potential role of bEVs on BP was also evaluated in Dahl S and obstructive sleep apnea models of hypertension. Significant differences were observed in WKY and SHRSP bEV cargo, including small RNAs, proteins, and PAMPs (pathogen-associated molecular patterns). Transplantation of SHRSP bEVs to WKY rats increased renal sympathetic nerve activity and elevated BP. Moreover, we showed that bEVs influence BP regulation in Dahl S and obstructive sleep apnea-induced hypertension. Our findings position bEVs as critical mediators of microbiota-host communication in BP regulation and demonstrate that bEVs from the altered SHRSP microbiota promote hypertension. Our findings shed new light on the role of bEVs in hypertension pathogenesis and offer new perspectives for diagnostics and therapeutic interventions.

Proteinuria is a key marker of renal damage and is often associated with hypertension and increased cardiovascular risk. This study reviews and brings the potential involvement of renal nerves in the pathophysiology of proteinuria and renal impairment in clinical and experimental studies. Studies have highlighted that increased activation of renal sympathetic and sensory nerves activity either alone or in combination with the renin-angiotensin-aldosterone system (RAAS) contributes to the development of proteinuria and the decline in renal function. This phenomenon may occur through mechanisms that alter glomerular and/or tubular function. Additionally, interventions aimed at disrupting renal nerve activity, including pharmacological agents and surgical denervation, or RAAS blockade demonstrated a significant reduction in proteinuria and improved renal and cardiovascular outcomes. Here, we highlight the potential roles of renal nerves beyond their traditional effects on renal function, such as albumin reabsorption, glomerular function, and renal damage, in the onset and maintenance of cardiovascular disease and hypertensive nephropathy.

Neuromedin U in paraventricular nucleus enhances adipose afferent reflex and sympathoexcitation via the activation of receptor-ERK signaling pathway in rats with obesity-related hypertension.

Congestive heart failure (CHF) is characterized by the activation of neurohumoral drive concomitant with avid fluid retention. Renal denervation alleviates this fluid retention. SGLT2 (sodium-glucose cotransporter 2) inhibitors have shown remarkable improvement in patients with cardiovascular diseases. We have recently demonstrated a relationship between enhanced renal sympathetic nerve activity and SGLT2 expression as well as function during CHF; however, the precise molecular mechanisms involved in the expression and translocation of SGLT2 and associated scaffolding proteins to the luminal membrane remain to be examined. CHF was induced by coronary artery ligation followed by bilateral renal denervation 4 weeks later, in rats. Western blot analysis and immunohistochemistry were performed to evaluate changes in the expression of SGLT2, MAP17 (membrane-associated protein 17), PDZK1 (PDZ domain containing 1), and activation of ERK (extracellular signal-regulated kinase)/NF-KB (nuclear factor κB) in renal cortex. Human adult proximal tubular cells were used to determine the direct effect of norepinephrine on the expression of SGLT2-MAP17-PDZK1 and activation of the ERK/NF-KB pathway. Rats with CHF exhibited significantly enhanced expression of SGLT2, MAP17, and PDZK1 with a concomitant significant activation of ERK and NF-KB in the renal cortex. In rats with CHF, renal denervation mitigated enhanced expression of SGLT2-MAP17-PDZK1 as well as activation of ERK and NF-KB. Direct action of norepinephrine on human adult proximal tubular cells cells triggered enhanced expression of SGLT2-MAP17-PDZK1 by the activation of the ERK/NF-KB pathway. Enhanced basal renal sympathetic nerve activity in CHF activates the ERK/NF-KB pathway, which in turn facilitates the enhanced expression and translocation of the SGLT2-MAP17-PDZK1 scaffolding protein complex to the luminal membrane, augmenting sodium reabsorption in CHF.

Excessive oxidative stress within the renal medulla is implicated in the development of hypertension, potentially modulated by renal nerve stimulation (RNS). This study examined the effects of RNS on cortical and medullary blood perfusion in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP) under both normal conditions and at varying levels of oxidative stress. Male SHRSP rats were assigned to five experimental groups and subjected to RNS at different frequencies, with infusions of vehicle, tempol, tempol plus catalase (tem + cat), diethyldithiocarbamic acid (DETC), or L-nitro-arginine methyl ester (L-NAME) at the renal cortico-medullary border (CMB). Regional blood perfusion of the renal cortex and medulla (CBP and MBP, respectively) was assessed using Laser-Doppler flowmetry. RNS significantly reduced CBP and MBP by 43 ± 8% and 23 ± 4%, respectively, at 8 Hz. Co-infusion of tempol plus catalase significantly attenuated the RNS-induced reductions in both CBP and MBP. Similarly, DETC infusion mitigated RNS-induced decreases in CBP and MBP. In contrast, tempol alone and L-NAME did not protect against the RNS-induced under-perfusion of the renal cortex and medulla. The results suggest that simultaneous removal of superoxide anion and hydrogen peroxide (H2O2) can alleviate the reduction in renal blood perfusion caused by RNS, emphasizing a crucial role for H2O2 in renal hemodynamic regulation. Interestingly, DETC, which is expected to elevate superoxide anion levels, also mitigated RNS-induced under-perfusion, suggesting the presence of a potentially novel indirect protective mechanism that warrants further investigation.

Refractory hypertension is a common and serious complication in patients with end-stage renal disease (ESRD), and conventional medications and catheter-based renal denervation (RDN) have limited efficacy in some patients. Laparoscopic-based renal sympathetic nerve denervation (L-RDN), an emerging noninvasive treatment, may offer new treatment options for selected patients by directly exposing the outer surface of the renal artery for ablation. This study enrolled 3 patients with ESRD and refractory hypertension who underwent L-RDN. Postoperatively, blood pressure was monitored to assess the changes before and after the procedure, as well as to evaluate the feasibility, safety, and short-term efficacy of this intervention. All 3 patients successfully underwent surgical treatment. Postoperative follow-up revealed that 2patients completed a full 12-month follow-up, while the remaining patient completed a 6-month interim follow-up. Blood pressure levels in all patients were significantly reduced compared to preoperative levels 1 week after surgery and remained relatively stable throughout the follow-up period. Specifically, the systolic and diastolic blood pressures of the 3 patients decreased by an average of 25 and 21 mmHg, respectively, at 1 week postoperatively, and no significant rebound or fluctuation in blood pressure was observed during the follow-up period. One patient developed a lymphatic fistula 1 month after surgery, which was successfully managed with conservative treatment, while the other 2 patients experienced no significant postoperative complications. This result suggests that the procedure is effective in significantly reducing blood pressure in the short term and may contribute to long-term blood pressure stabilization. This case series demonstrates that L-RDN may represent a safe and effective therapeutic modality, offering a potential alternative treatment option for patients with vascular pathologies or contraindications to intravascular interventions. However, given the limited sample size, further prospective studies are necessary to validate its long-term efficacy and safety.

While sympathetic overactivity is a well-established driver of disease progression in heart failure with reduced ejection fraction, its role in early-stage heart failure with preserved ejection fraction (HFpEF) remains unclear. In particular, renal sympathetic activity-an important contributor to neurohormonal dysregulation-has not been systematically evaluated in HFpEF. Early-stage HFpEF refers to patients who present with mild symptoms, only modest elevations in B-type natriuretic peptide (BNP), and invasively confirmed elevated left ventricular end-diastolic pressure (LVEDP) but without overt structural remodeling or severe congestion. We conducted a single-center retrospective randomized controlled study including 121 patients with early-stage HFpEF and 44 matched controls. All participants underwent 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy to quantify sympathetic nerve activity in the heart and kidneys. Uptake ratios (15min and 4h heart-to-mediastinum [H/Ma] and kidney-to-posterior mediastinum [K/Mp]) and washout rates (Heart Washout Rate [HWR] and Kidney washout Rate [KWR]) were calculated. Correlations with these MIBG parameters and left ventricular end-diastolic pressure (LVEDP) were analyzed. HFpEF patients showed significantly higher cardiac H/Ma and renal K/Mp ratios, and lower HWR and KWR compared with controls (all P < 0.001). In the HFpEF group, both 4-h H/Ma and 4-h K/Mp ratios were positively correlated with LVEDP, while HWR and KWR were inversely correlated with these indices (all P < 0.01). Early-stage HFpEF patients show increased cardiac and renal sympathetic activity, highlighting the renal sympathetic nervous system as a potential therapeutic target and suggesting 131I-MIBG scintigraphy as a promising tool for risk stratification and early intervention.

Over one-third of Canadians with hypertension do not achieve recommended blood pressure (BP) targets despite availability of effective treatments. Renal sympathetic nerve denervation (RDN) is a recently approved, minimally invasive treatment for hypertension being offered in multiple Canadian centers. How best to implement this procedure in contemporary Canadian clinical practice remains unclear. Herein, we provide a Canadian hypertension specialist viewpoint on use of RDN in Canada. We review the rationale for, and evidence supporting, the use of RDN and discuss, using two clinical cases, its potential therapeutic role. We note that RDN has effectively lowered BP in multiple, sham-controlled, randomized clinical trials and has a favourable safety profile. Economic modeling estimates that it is cost-effective in the Canadian context. Conversely, the BP lowering effect is relatively modest; no well-established method to pre-identify responders exists; cardiovascular endpoint data supporting use of RDN are lacking; and no clear funding model is currently in place in Canada. Accordingly, we suggest that use of RDN be reserved for willing patients with severely elevated BP despite the use of first-line conventional therapies who have had secondary causes excluded. Examples include patients with resistant hypertension or moderate or severe hypertension and multiple drug intolerance syndrome. In view of its recent approval and known operator-dependency, RDN should be offered solely through programmatic, multidisciplinary collaboration between hypertension specialists and experienced interventionalists using a shared decision-making approach with the patient. Funding deployment should target such programs and sites should carefully monitor their outcomes to confirm comparability to the published literature.

Safety and Efficacy of Renal Sympathetic Denervation Using Percutaneous Radiofrequency Ablation, a New Hypertension Treatment.

SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation.

BackgroundChronic overactivity of the renal nerves is a key pathophysiological attribute of drug-resistant hypertension. Indeed, catheter-based renal denervation can lower blood pressure by severing the brain-kidney (efferent nerves) and kidney-brain (afferent nerves) link, but its irreversibility and potential nerve reconnection limits adaptability and longevity, highlighting the need for alternative treatments. Kilohertz-frequency electrical stimulation is an approach known to reversibly inhibit peripheral nerve activity and has potential to reversibly modulate renal blood flow.MethodsThis study investigated how electrical stimulation of the renal nerves affects renal blood flow in a non-diseased anesthetized swine. Using unilateral hook electrodes around the renal artery-nerve complex, we performed parameter sweeps of stimulation frequency (20–15000 Hz) and measured blood flow and blood pressure changes in the ipsilateral kidney.ResultsStimulation at low frequencies (≤ 100 Hz) resulted in a sustained reduction in renal blood flow. High stimulation frequencies (> 100 Hz) often resulted in an immediate decrease in blood flow through the kidneys, but the responses exhibited adaptation with continued isochronal pulsatile stimulation. Notably, while kilohertz-frequency stimulation did not directly increase renal blood flow in this experiment, it did induce a carryover effect on renal nerve sensitivities to low-frequency stimulation, reducing the effect of subsequent low-frequency stimulation on renal blood flow (from − 11.8% to -4.7%, median).ConclusionsResponses to renal nerve stimulation depend on stimulation frequency with effects that can persist or adapt as well as effects that can range from decreasing renal blood flow to decreasing the sensitivity of the renal nerve signaling pathway. These findings have important implications for future development of bioelectronic interfaces with the renal nerve for modulation of kidney function.Supplementary InformationThe online version contains supplementary material available at 10.1186/s42234-025-00192-7.

IntroductionChemical ablation of renal sensory nerves using agonists for transient receptor potential vanilloid-1 (TRPV1) lowers arterial blood pressure (ABP) in multiple experimental models of hypertension. Interestingly, both afferent renal nerve activity and arterial blood pressure were significantly attenuated in male Trpv1−/− rats after 2-kidney-1-clip (2K1C) renovascular hypertension. However, TRPV1 expression in sensory neurons differs across species and is lower in mice versus rats or humans. Therefore, the current study assessed the proportion of TRPV1 in mouse renal sensory neurons and tested whether deletion of TRPV1 altered renovascular hypertension in mice.Methods2K1C surgery was performed by placement of a 0.5mm length of polyetrafluoroethylene tubing around the right renal artery. Experiment 1 quantified the proportion of TRPV1 mouse renal sensory neurons in both sham and 2K1C after a kidney injection of the tracer wheat germ agglutinin conjugated to AlexaFluor 647. Experiment 2 assessed ABP using telemetry in WT and Trpv1−/− mice after 2K1C.ResultsFirst, the majority of retrogradely labeled neurons were located in the ipsilateral T10-L2 dorsal root ganglion and small to medium sized (10-29um diameter). Approximately 60% were TRPV1-positive. Second, 2K1C significantly increased ABP in both male and female WT and Trpv1−/− mice. However, the magnitude of the hypertension was not statistically different between strain and sex. Depressor responses to ganglionic blockade also did not differ between strains and sex.ConclusionThese findings suggest that a subset of renal sensory neurons in the mouse are TRPV1-positive, and renovascular 2K1C hypertension is not attenuated in the Trpv1−/− mouse.

While renal denervation (RDN) represents a promising therapy for resistant hypertension, substantial heterogeneity in blood pressure-lowering efficacy and a significant treatment non-response rate (reaching up to one-third of cases) impede its broader clinical adoption. This variability likely arises from two primary sources: interindividual differences in sympathetic nervous system activation among hypertensive patients (the pathological substrate for ablation) and procedural limitations ("black-box procedure") leading to incomplete sympathetic denervation. Our comprehensive review synthesizes recent advances in precision patient selection and procedural refinement for RDN. Furthermore, we propose a conceptual framework aimed at enhancing therapeutic consistency through the integrated optimization of patient stratification and ablation techniques. We believe this work provides insights to support the reliable clinical translation of RDN. Key strategies to improve treatment response to RDN. Notes: RDN, renal denervation; HR, heart rate; BRS, baroreflex sensitivity; PWV, pulse wave velocity; AASI, arterial stiffness index; TAC, total arterial compliance; RNS, renal nerve stimulation.

This study investigated the role of brain AT1 and AT2 receptors and the nitric oxide (NO) system in modulating renal sympathetic nerve activity (RSNA) baroreflex in unanaesthetised rats. Baroreflex gain curves (BRC) were generated following intracerebroventricular (I.C.V.) infusion of saline, Ang II, or Ang II combined with either losartan, PD123319 (AT2 antagonist), or L-NAME (NO synthase inhibitor). An AT2 agonist (CGP42112) was also infused I.C.V. with L-NAME. RSNA baroreflex sensitivity increased by 60% (P = 0.004) following losartan compared to saline (-4.8 ± 1.9 vs. -3.0 ± 0.9), but not after CGP42112. I.C.V. Ang II increased maximum gain by ~ 70% (P = 0.003) compared to saline (-5.0 ± 1.6 vs. -3.0 ± 0.9). This effect was reversed when Ang II was co-infused with PD123319 (-3.7 ± 1.1), but not losartan. I.C.V. CGP42112 increased the overall response range of the baroreflex but lowered the minimum level it could reach compared to saline (P = 0.03 - 0.02). The baroreflex effects of I.C.V. CGP42112 (P = 0.013), but not Ang II, were abolished when co-infused with L-NAME. These findings demonstrate an important facilitatory role for AT2 in baroreflex regulation of RSNA in unanaesthetised rats at basal brain levels of Ang II, a mechanism that is dependent on a functional NO system. By contrast, AT1 exerts an inhibitory effect on the baroreflex that is independent of NO. These observations suggest that targeting central AT2 receptors may represent a potential therapeutic strategy for conditions such as neurogenic hypertension, where impaired baroreflex function is present.

Chronic kidney disease is marked by increased sympathetic activity, inflammation, RAAS activation, and oxidative stress, promoting necroptosis. This study explores the potential of co-administering yohimbine and sodium hydrosulfide (NaHS) to reduce necroptosis, possibly by modulating RAAS/ROS imbalance, sympathetic overactivity, and inflammation. Male rats were assigned to five groups (n = 8): Sham, CKD, CKD + yohimbine, CKD + NaHS, and CKD + yohimbine + NaHS. CKD was induced via daily intraperitoneal adenine injections (50mg/kg) for 4weeks. After CKD induction, treatments included yohimbine (0.3mg/L) and/or NaHS (15μmol/L) in drinking water for another 4weeks. After 8weeks, urine samples were collected, and renal sympathetic nerve activity (RSNA), renal function, RAAS and norepinephrine levels, oxidative stress, inflammation, and necroptosis-related protein expression were assessed. CKD induction disrupted renal function and intensified RAAS/ROS imbalance, sympathetic overactivity, inflammation, and necroptosis through RIPK1-MLKL axis activation. Yohimbine alone reduced renal sympathetic nerve activity by approximately 18% and norepinephrine levels by 9% (p < 0.05). NaHS alone decreased plasma angiotensin II level by 9% (p < 0.05). Co-administration improved these three indices plus kidney function, oxidative stress and inflammation markers; downregulated angiotensin II Type I Receptor (AT1R), RIPK1, and MLKL proteins; and upregulated caspase-8 (p ≤ 0.05). In CKD, the interconnected RAAS/ROS imbalance and sympathetic-driven inflammation may activate necroptosis via the RIPK1-MLKL axis. Co-treatment with yohimbine and NaHS appeared to attenuate necroptosis, potentially by interfering with these pathological loops. Further studies are warranted to confirm these findings and elucidate the underlying mechanisms.

This study investigates the role of renal nerve afferents in sympathetic vasomotor responses during acute low-dose furosemide administration intravenously or directly in the renal pelvis. We hypothesized that furosemide activates renal nerve afferents, modulating sympathetic vasomotor activity. To test this hypothesis, we conducted simultaneous recordings of renal sympathetic nerve activity (rSNA) and splanchnic sympathetic nerve activity (sSNA) in Wistar rats. The effects of intravenous furosemide infusion (1 mg/kg/h) on mean arterial pressure, heart rate, rSNA, and sSNA in control (CTRL, n = 5) and afferent renal denervated rats (ARD, n = 5) were investigated. In addition, we infused furosemide (from 10 to 100 µg/mL; 200 µL) directly in the renal pelvis (n = 8), with simultaneous recordings of hemodynamic parameters and sympathetic nerve activity. Furosemide induced a significant reduction in rSNA (spikes/s) but not in sSNA in the ARD compared with the CTRL group (rSNA maximal decrease of 21 ± 7 in ARD vs. a maximal increase of 27 ± 13 spikes/s in CTRL at 120 min, *P < 0.05), as well as in the amplitude of bursts (rSNA -0.21 ± 0.072 vs. 0.062 ± 0.16 mVs at 120 min, *P < 0.05). Moreover, intrapelvic furosemide infusion in CTRL rats preferentially increased rSNA (69% of the maximal response induced by capsaicin); as for sSNA, there was no significant difference. These findings suggest that transient receptor potential vanilloid type-1-expressing C-fiber afferents, located in the renal pelvis, are activated by furosemide, leading to a preferential change in the pattern of sympathetic activity to the kidneys, independently of blood volume depletion.NEW & NOTEWORTHY 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).

Abstract Introduction Chronic kidney disease (CKD) exacerbates heart failure through cardiorenal interactions, yet the underlying mechanisms remain unclear. Sympathoexcitatoin plays a crucial role in heart failure development. Renal injury increases the activity of afferent sensory nerves from the kidney to the sympathetic centres in the brain, and acute stimulation of these afferent renal nerves may enhance sympathetic outflow. Thus, afferent nerve input from the kidney to the brain may contribute to cardiorenal interaction. However, the widely used 5/6 nephrectomy CKD model is inadequate for studying kidney-brain neural mechanisms, as it involves the removal of one kidney and its renal nerves. Purpose This study aimed to develop a novel CKD model that preserves both kidneys and their renal nerves and to investigate its cardiac phenotype. Methods Male C57BL/6J mice were used. On Day 1, the surface of one kidney’s upper and lower poles was ablated using an electric heating wire. On Day 8, the same procedure was performed on the contralateral kidney. On Day 36, renal function and cardiovascular parameters were assessed. Results On Day 36, BUN and serum creatinine levels were significantly higher in ablated mice than in sham controls (BUN: 90.9 ± 4.7 vs. 29.0 ± 1.4 mg/dL; creatinine: 0.295 ± 0.023 vs. 0.095 ± 0.005 mg/dL; n = 6 vs. n = 4; p &amp;lt; 0.05). Urine albumin, and the urine albumin-to-creatinine ratio (UACR) were also significantly increased in ablated mice (urine albumin: 29.3 ± 8.7 vs. 1.2 ± 0.3 μg/24 hr; UACR: 0.474 ± 0.205 vs. 0.027 ± 0.004 μg/g; n= 6 vs. 4; p &amp;lt; 0.05). There were no significant differences in systolic blood pressure or heart rate (systolic blood pressure: 111.9 ± 2.6 vs. 104.2 ± 1.6 mmHg; heart rate: 638.5 ± 20.0 vs. 599.5 ± 23.2 bpm; n= 6 vs. 4) between the groups. Echocardiographic data showed a significant increase in E/e’ (49.1 ± 8.6 vs. 25.3 ± 1.9; n=3 vs. n=3; p &amp;lt; 0.05), whereas left ventricular wall thickness (intraventricular septum thickness + posterior wall thickness: 1.71 ± 0.05 vs. 1.71 ± 0.21 mm), ejection fraction (72.2 ± 4.5 vs. 68.2 ± 0.7%), and E/A ratio (2.21 ± 0.18 vs. 1.70 ± 0.14) showed no significant differences. Conclusions and Perspectives This kidney surface ablation model provides a more physiologically relevant CKD model by preserving partial renal function in both kidneys. Additionally, it enables the study of CKD-induced cardiac dysfunction, as diastolic dysfunction was observed four weeks after CKD induction. Future studies will examine whether this model exacerbates heart failure when combined with heart failure models, such as a myocardial infarction model. Furthermore, renal afferent nerve denervation will help clarify the role of neurogenic renal afferent input in the pathophysiology of heart failure with concomitant CKD.