Increase In Renal Vascular Resistance Research Articles

EARLY FLUID PLUS NOREPINEPHRINE RESUSCITATION DIMINISHES KIDNEY HYPOPERFUSION AND INFLAMMATION IN SEPTIC NEWBORN PIGS.

Sepsis is the most frequent risk factor for acute kidney injury (AKI) in critically ill infants. Sepsis-induced dysregulation of kidney microcirculation in newborns is unresolved. The objective of this study was to use the translational swine model to evaluate changes in kidney function during the early phase of sepsis in newborns and the impact of fluid plus norepinephrine resuscitation. Newborn pigs (3-7-day-old) were allocated randomly to three groups: 1) sham, 2) sepsis (cecal ligation and puncture) without subsequent resuscitation, and 3) sepsis with lactated Ringer plus norepinephrine resuscitation. All animals underwent standard anesthesia and mechanical ventilation. Cardiac output and glomerular filtration rate were measured noninvasively. Mean arterial pressure, total renal blood flow, cortical perfusion, medullary perfusion, and medullary tissue oxygen tension (mtPO 2 ) were determined for 12 h. Cecal ligation and puncture decreased mean arterial pressure and cardiac output by more than 50%, with a proportional increase in renal vascular resistance and a 60-80% reduction in renal blood flow, cortical perfusion, medullary perfusion, and mtPO 2 compared to sham. Cecal ligation and puncture also decreased glomerular filtration rate by ~79% and increased AKI biomarkers. Isolated foci of tubular necrosis were observed in the septic piglets. Except for mtPO 2 , changes in all these parameters were ameliorated in resuscitated piglets. Resuscitation also attenuated sepsis-induced increases in the levels of plasma C-reactive protein, proinflammatory cytokines, lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, and renal NLRP3 inflammasome. These data suggest that newborn pigs subjected to cecal ligation and puncture develop hypodynamic septic AKI. Early implementation of resuscitation lessens the degree of inflammation, AKI, and liver injury.

351 Can Exogenous Ketones Prevent the Effects of High Salt Intake on Renal Vascular Resistance During Sympathoexcitation?

OBJECTIVES/GOALS: Renal vascular resistance (RVR) is the opposition to blood flow by renal arteries. At the population level, dietary salt increases RVR and blood pressure (BP), which are associated with cardiovascular disease. Recent data indicate exogenous ketones may offset adverse cardiorenal effects of salt. METHODS/STUDY POPULATION: Our registered clinical trial (NCT05545501) is a double-blinded, placebo-controlled, crossover study. Participants are being randomized to three 10-day conditions: A) control; B) high salt; C) high salt and ketone supplementation. Ten participants are enrolled (target 30 participants). Renal blood velocity (RBV) in the renal and segmental arteries will be measured in the decubitus position using Doppler ultrasound during a 3-minute baseline and 3-minute cold pressor test. We will measure brachial BP with an automated oscillometric BP monitor. RVR will be calculated as mean BP divided by RBV. Statistical analyses will include ANOVA and correlations with α set at ≤ 0.05. RESULTS/ANTICIPATED RESULTS: We anticipate attenuated RBV and increased BP during the cold pressor test, particularly following high salt loading, leading to greater RVR. We hypothesize ketone supplementation will attenuate the high salt induced increase in RVR during the cold pressor test. In addition to RVR we will examine renal vascular conductance which is the ease with which blood flows through arteries, calculated as RBV divided by mean BP. Additional hemodynamics such as heart rate and systolic and diastolic BP will be reported and correlated with primary outcomes. DISCUSSION/SIGNIFICANCE: Dietary salt plays a role in hypertension, cardiovascular disease, and chronic kidney disease, which are leading causes of death. Ketone supplementation may be a promising approach to counteract the detrimental effects of high dietary salt and improve cardiovascular health in adults.

Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.

In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI.

Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences

Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences

Diet-induced hypertension in rats is associated with increased renal vasoconstrictor response to angiotensin II after imitated endothelial dysfunction.

The mechanisms behind development of diet-induced hypertension remain unclear. The kidneys play a paramount role in blood volume and blood pressure regulation. Increases in renal vascular resistance lead to increased mean arterial blood pressure (MAP) due to reduced glomerular filtration rate and Na+ excretion. Renal vascular resistance may be increased by several factors, e.g. sympathetic output, increased activity in the renin-angiotensin system or endothelial dysfunction. We examined if a 14-week diet rich in fat, fructose or both led to increased renal vascular resistance and blood pressure. Sixty male Sprague-Dawley rats received normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat + Fruc) for 14weeks from age 4-weeks. Measurements included body weight (BW), telemetry blood pressures, renal blood flow in anesthetized rats, plasma concentrations of atrial natriuretic peptide and glucose, as well as vessel myography in renal segmental arteries. Body weight increased in both groups receiving high fat, whereas MAP increased only in the High Fat + Fruc group. Renal blood flow did not differ between groups showing that renal vascular resistance was not increased by the diets. After inhibiting nitric oxide and prostacyclin production, renal blood flow reductions to Angiotensin II infusions were exaggerated in the groups receiving high fructose. MAP correlated positively with heart rate in all rats tested. Our data suggest that diet-induced hypertension is not caused by an increase in renal vascular resistance. The pathophysiological mechanisms may include altered signaling in the renin-angiotensin system and increases in central sympathetic output in combination with reduced baroreceptor sensitivity leading to increased renal vasoconstrictor responses.

Mechanical stretch‐driven ROS generation stimulates endothelin production in neonatal pig renal epithelial and vascular endothelial cells

The circulating level of endothelin (ET), a potent vasoactive peptide, decreases with postnatal age. ET is also of pathophysiological significance in the kidney. ET is generated via endothelin converting enzyme (ECE)‐induced proteolytic processing of pro‐molecule big ET to biologically active peptides. Hydrogen peroxide (H2O2), a reactive oxygen species (ROS), transactivates the promoter of ECE1. Oxyradicals contribute to kidney pathophysiology, but whether ROS regulates ET production in the kidneys remains unresolved. The present study shows that ECE1 is the predominant isoform in neonatal pig kidneys. We also demonstrated that H2O2 induces ECE1‐dependent ET1‐3 production in the neonatal pig renal proximal tubules (PT) and vascular endothelial cells (EC). A uniaxial stretch of neonatal pig PT and EC increased NADPH oxidase (NOX) 2 and 4 levels and stimulated H2O2production. Mechanical stretch increased cellular ECE1 production in the PC and EC cells, which catalase mimetic EUK 134 and NOX inhibitor apocynin reversed. Mechanical stretch also triggered cellular ET1‐3 generation in PT and EC. Mechanical stretch‐induced ET1‐3 production was attenuated by EUK 134, apocynin, and a selective ECE1 inhibitor CGS 35066. Short‐term unilateral urinary tract obstruction (UUO), an inducer of the mechanical stretch of kidney cells and oxyradical production, increased ECE1‐dependent ET1‐3 production in neonatal pig kidneys. Despite removing the obstruction, acute UUO generated ROS, reduced kidney perfusion, and increased renal vascular resistance (RVR). UUO also elevated early biomarkers of acute kidney injury (AKI). Inhibition of ECE1 and ET receptors protected against UUO‐induced increase in RVR and early AKI. These data suggest that mechanical stretch‐driven ROS generation stimulates ET production in neonatal pig renal epithelial and vascular endothelial cells. ET then promotes AKI by causing renal hypoperfusion. This signaling pathway may underlie UUO‐induced renal insufficiency in infants.

Polyethylene glycol‐20 ameliorates tissue ischemia and improves renal function following traumatic shock

The “Golden Hour” policy used for US Troops in Iraq and Afghanistan has contributed to the highest survival rates for combat injury in history. Anticipated future combat operations require more options to optimize combat casualty care by extending “the Golden Hour” to “the Golden Day.” Low volume resuscitation with polyethylene glycol‐20K (PEG) has been shown to decrease mortality following hemorrhagic shock, however, the effect of PEG on tissue perfusion and renal function has not been determined. We hypothesized that PEG can ameliorate ischemia and prevent renal injury during prolonged traumatic shock. Anesthetized rats received extremity trauma (soft tissue injury and fracture in one hindlimb) and pressure‐controlled hemorrhage, with mean arterial pressure (MAP) maintained at 55mmHg. MAP, heart rate, renal blood flow (RBF, perivascular ultrasonic transit time flow probe), peripheral skeletal muscle microcirculatory flow and tissue oxygen partial pressure (OxyLite needle probes), blood gases, and electrolytes were monitored throughout the experiment. Glomerular filtration rate (GFR) was recorded using a non‐invasive Fluorescein isothiocyanate‐sinistrin transcutaneous technique. After 45 minutes of shock with MAP at 55mmHg, rats were randomly treated with an intravenous bolus of either 7.5% PEG or saline (1.3 ml/kg, n = 5/group). Measurements were continued from the 45th to the 165th minute without MAP control or any other treatment. Compared with saline, PEG markedly improved MAP recovery (P < 0.001) and survival (P < 0.01) (Figures 1A and 1B). Microcirculatory perfusion and oxygen partial pressure were markedly decreased after hemorrhage and saline treatment elicited no additional effect. However, with PEG, the decreases in capillary flow and tissue oxygen levels were significantly attenuated (P = 0.04 and 0.03, respectively) (Figure 2A). Moreover, blood lactate levels continuously increased in the saline group but returned to levels comparable to baseline within 30 minutes after PEG treatment (P < 0.001) (Figure 2B). In the saline group, RBF markedly decreased concomitantly with a sustained increase in renal vascular resistance (RVR) during the shock period. PEG treatment rapidly restored RBF (P < 0.001) to levels comparable to baseline along with a normalized RVR. GFR was diminished in the saline‐treated rats but was improved in the PEG‐treated group (0.07 ± 0.05 vs. 0.67 ± 0.06 ml/min/100g, respectively; P < 0.001). These results provide strong evidence that PEG rapidly improves macro‐ and microcirculatory hemodynamics ameliorates tissue ischemia, and minimize renal injury and mortality following prolonged traumatic shock.

Change in renal hemodynamics after renal denervation in diabetic patients with resistant hypertension and chronic kidney disease

Abstract Background There are very few data on the initial features of hemodynamics and its changes after renal denervation (RDN) in patients with resistant hypertension (RHTN) and type 2 diabetes mellitus (DM), depending on the presence of chronic kidney disease (CKD), and the mechanisms of this effect require further study. Purpose To assess the features of renal hemodynamics and its change after RDN in patients with RHTN with type 2 DM, depending on the presence or absence of CKD. Methods In the study were included 38 patients with RHTN with type 2 DM (mean age 60.6±8.1 years, 14 men, 24-hour systolic / diastolic blood pressure (24-hr SBP/DBP) 160.9±16.5 / 82.2±11.3 mm Hg, mean HbA1c 7.87±1.62%), of which CKD occurred in 18 pts. (eGFR – 47.1 ml/min/1.73 m2), and 20 pts. without CKD (eGFR – 80.3 ml/min/1.73m2). All patients underwent baseline office and 24-hr BP measurement with calculation DBP/SBP ratio (D/S ratio), Doppler ultrasonography, serum creatinine, estimated glomerular filtration rate (eGFR) (CKD-EPI formula), urinary albumin excretion (UAE). The six-month follow-up period was completed by 14 patients in the group with CKD and 18 patients without CKD. Results At baseline, patients with CKD compared with those without CKD had higher pulse BP (82.2±10.0 versus 75.6±15.9, p=0.061), renal resistive indices (RRI) (0.78±0.06 versus 0.69±0.05, p=0.001 in the main renal arteries (RA); 0.73±0.07 versus 0, 63±0.06, p=0.001 in segmental RA) and significantly lower level of D/S ratio (0.49±0.06 versus 0.53±0.06, p=0.040). At the same time, the frequency of increased RRI (>0.70) in the CKD group was almost 14 times higher than in those without CKD (73% and 5.3%, respectively, p<0.001).After RDN, patients with CKD showed a significant decrease in SBP (−10.7 mm Hg, p=0.008) and an insignificant decrease in DBP (−3.9 mm Hg, p=0.118). In group without CKD, on the contrary, there was an insignificant decrease in SBP (−7.6 mm Hg, p=0.102) and a significant decrease in DBP (−5.5 mm Hg, p=0.030). The D/S ratio tended to increase in the group of CKD patients (p=0.08), whereas these indicators did not change significantly in the group without CKD. Additionally, there were a positive dynamics of RRI (decrease >0.05) in patients with CKD, the frequency of which was almost 4 times higher than that in persons without CKD (43% and 11%, respectively, p=0.049). Moreover, a decrease in RRI correlated with an increase in the D / S ratio of both the main RA (R = 0.50; p=0.005) and in segmental RA (R = 0.40; p=0.028). There were no significant changes in UAE and serum creatinine in both groups. Conclusions Thus, CKD in patients with RHTN with type 2 DM is characterized by a significant increase in renal vascular resistance, while RDN in this patients, in contrast to patients without CKD, can be an effective therapeutic option not only for BP reduction, but also for improvement of renal hemodynamics. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Russian Foundation for Basic Research

Extremity trauma exacerbates acute kidney injury following prolonged hemorrhagic hypotension.

The incidence of and mortality due to acute kidney injury is high in patients with traumatic shock. However, it is unclear how hemorrhage and trauma synergistically affect renal function, especially when timely volume resuscitation is not available. We hypothesized that trauma impairs renal tolerance to prolonged hemorrhagic hypotension. Sprague-Dawley rats were randomized into six groups: control, extremity trauma (ET), hemorrhage at 70 mm Hg (70-H), hemorrhage at 55 mm Hg (55-H), ET + 70 mm Hg (70-ETH), and ET + 55 mm Hg (55-ETH). Animals were anesthetized, and ET was induced via soft tissue injury and closed fibula fracture. Hemorrhage was performed via catheters 5 minutes after ET with target mean arterial pressure (MAP) clamped at 70 mm Hg or 55 mm Hg for up to 3 hours. Blood and urine samples were collected to analyze plasma creatinine (Cr), Cr clearance (CCr), renal oxygen delivery (DO2), urinary albumin, and kidney injury molecule-1 (KIM-1). Extremity trauma alone did not alter renal hemodynamics, DO2, or function. In 70-H, CCr was increased following hemorrhage, while Cr, renal vascular resistance (RVR), KIM-1, and albumin levels remained unchanged. Compared with 70-H, ET + 70 mm Hg exhibited increases in Cr and RVR with decreases in CCr and DO2. In addition, ET decreased the blood volume loss required to maintain MAP = 70 mm Hg by approximately 50%. Hemorrhage at 55 mm Hg and ET + 55 mm Hg exhibited a marked and similar decrease in CCr and increases in RVR, Cr, KIM-1, and albumin. However, ET greatly decreased the blood volume loss required to maintain MAP at 55 mm Hg and led to 50% mortality. These results suggest that ET impairs renal and systemic tolerance to prolonged hemorrhagic hypotension. Thus, traumatic injury should be considered as a critical component of experimental studies investigating outcomes and treatment following hemorrhagic shock. This is an original article on basic science and does not require a level of evidence.

Protection of coenzyme Q10 against contrast-induced acute kidney injury in male diabetic rats

BackgroundDiabetes mellitus (DM) is a major risk factor for contrast-induced acute kidney injury (CI-AKI). DM and CI-AKI result in oxidative damage and inflammation that can be reduced when treated with the coenzyme Q-10 (CoQ10). The aim of this study was to investigate the therapeutic potential of CoQ10 in renal function, renal hemodynamics, oxidative profile and renal histology in diabetic rats subjected to CI-AKI.MethodsWistar rats, male, randomized into five groups: citrate: control animals received citrate buffer (streptozotocin vehicle, 0.4 mL); Tween: control animals of CoQ10 treatment received 1% Tween 80 (CoQ10 vehicle, 0.5 mL); DM: animals that received streptozotocin (60 mg/kg); DM + IC: DM animals treated with iodinated contrast (IC, 6 mL/kg); DM + IC + CoQ10: DM animals treated with CoQ10 (10 mg/kg) and that received IC (6 mL/kg). The protocols lasted 4 weeks. An evaluation was made to measure renal function, inulin clearance and serum creatinine, renal hemodynamics by renal blood flow (RBF) and renal vascular resistance (RVR), markers of oxidative stress such as urinary peroxides and nitrate, lipid peroxidation, thiols in renal tissue and renal histological analysis.ResultsDM animals showed reduced renal function, which was followed by an increase inserum creatinine and significant reduction of inulin clearance and RBF. It was noticed an increase in RVR and redox imbalance with higher urinary peroxides and nitrate lipid peroxidation levels with depletion of thiols in renal tissue. IC treatment exacerbated these changes in DM + IC. CoQ10 administration ameliorated renal function, prevented hemodynamic changes and neutralized oxidative damage and progression of the histologic damage in the DM + IC + CoQ10 group.ConclusionThis study demonstrated the renoprotection properties of CoQ10 in an experimental model of risk factor of DM for CI-AKI. CoQ10 presented an antioxidant effect on the CI-AKI in male diabetic rats by improving renal function and renal hemodynamics, preserving morphology and reducing oxidative stress.

Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice.

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.

Beneficial Effects of Isoflavones in the Kidney of Obese Rats Are Mediated by PPAR-Gamma Expression.

Several studies have demonstrated an important association between altered lipid metabolism and the development of kidney injury because of a high-fat diet. Fructose is also closely associated with renal injury. We opted for a combination of fructose and saturated fats in a diet (DH) that is a model known to induce renal damage in order to evaluate whether soy isoflavones could have promising use in the treatment of renal alterations. After two months of ingestion, there was an expansion of visceral fat, which was associated with long-term metabolic disorders, such as sustained hyperglycemia, insulin resistance, polyuria, dyslipidemia, and hypertension. Additionally, we found a decrease in renal blood flow and an increase in renal vascular resistance. Biochemical markers of chronic kidney disease were detected; there was an infiltration of inflammatory cells with an elevated expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β), the activation of the renin–angiotensin system, and oxidative/nitrosative stress. Notably, in rats exposed to the DH diet for 120 days, the concomitant treatment with isoflavones after 60 days was able to revert metabolic parameters, renal alterations, and oxidative/nitrosative stress. The beneficial effects of isoflavones in the kidney of the obese rats were found to be mediated by expression of peroxisome proliferator-activated receptor gamma (PPAR-γ).

Endothelins contribute to early renal insufficiency engendered by acute urinary tract obstruction in neonatal pigs

Urinary tract obstruction reduces kidney functions, which, if left uncorrected, may lead to irreversible renal loss, especially in infants. Despite the removal of obstruction, a decline in steady‐state renal blood flow (RBF) persists, vascular mechanisms of which are poorly understood. Urinary tract obstruction‐induced increase in the levels of vasoactive endothelin (ET)‐1 has been reported in humans and rodents. However, whether obstructive renal vasculopathy is associated with increased renal production of all ET isoforms (ET1‐3) remains unresolved. Also, the mechanisms that underlie ET‐induced renal vasoregulation in neonates are unclear. Here, we show that ET receptor (ETR)‐operated calcium entry via TRPC3 channels increases renal vascular resistance and reduces RBF in neonatal pigs. Acute unilateral urinary tract obstruction (UUO) in neonatal pigs increased peptidase endothelin converting enzyme 1 (ECE1)‐dependent renal production of ET1‐3 and diacylglycerol (DAG). Despite the removal of obstruction, acute UUO reduced kidney perfusion and caused an increase in renal vascular resistance (RVR) and the urinary levels of NGAL, the early predictive biomarker of acute kidney injury. The protein expression levels of ETRs (ETA and ETB) and TRPC3 channels in renal microvessels were unaltered in neonatal pigs subjected to acute UUO. However, pharmacological inhibition of ECE1, ETR, and TRPC3 mitigated acute UUO‐induced increase in RVR and urine NGAL in the pigs. These data suggest that increased ECE1 production and proteolytic processing of all big ETs to their vasoactive isoforms contribute to early neonatal renal insufficiency engendered by UUO. ET‐derived DAG activates renal vascular smooth muscle cell TRPC3 channels, leading to extracellular calcium entry, vasoconstriction, increased RVR and sustained hypoperfusionSupport or Funding InformationNIH/NIDDK: R01DK101668 and R56DK120595

Renal Nerve Deafferentation Attenuates the Fall in GFR during Intravenous Infusion of Furosemide in Anesthetized Rats

Introduction: Furosemide reduces the glomerular filtration rate (GFR) and increases the renal vascular resistance (RVR) despite inhibiting tubuloglomerular feedback but increases proximal tubule pressure, renin release, and renal nerve activity. Objective: This study tested the hypothesis that the fall in GFR with furosemide is due to volume depletion or activation of angiotensin type 1 (AT1) receptors or renal nerves. Methods: Furosemide was infused for 60 min at 1.0 mg·kg⁻¹·h⁻¹ in groups of 5–8 anesthetized rats. Additional groups received intravenous volume replacement to prevent fluid and Na⁺ losses or volume replacement plus losartan or plus sham denervation or plus renal denervation or renal nerve deafferentation. Results: At 60 min of infusion, furosemide alone reduced the GFR (–37 ± 4%; p < 0.01). This fall was not prevented by volume replacement or pretreatment with losartan, although losartan moderated the increase in RVR with furosemide (+44 ± 3 vs. +82 ± 7%; p < 0.01). Whereas the GFR fell after furosemide in rats after sham procedure (–31 ± 2%), it was not changed significantly after prior renal deafferentation. Proximal tubule pressure increased significantly but returned towards baseline over 60 min of furosemide, while urine output remained elevated, and GFR and renal blood flow depressed. Conclusions: The fall in GFR over 60 min of furosemide infusion is independent of volume depletion or activation of AT1 receptors but is largely dependent on renal afferent nerves.

Renal and segmental artery hemodynamics during whole body passive heating and cooling recovery.

High environmental temperatures are associated with increased risk of acute kidney injury, which may be related to reductions in renal blood flow. The susceptibility of the kidneys may be increased because of heat stress-induced changes in renal vascular resistance (RVR) to sympathetic activation. We tested the hypotheses that, compared with normothermia, increases in RVR during the cold pressor test (CPT, a sympathoexcitatory maneuver) are attenuated during passive heating and exacerbated after cooling recovery. Twenty-four healthy adults (22 ± 2 yr; 12 women, 12 men) completed CPTs at normothermic baseline, after passive heating to a rise in core temperature of ~1.2°C, and after cooling recovery when core temperature returned to ~0.2°C above normothermic baseline. Blood velocity was measured by Doppler ultrasound in the distal segment of the right renal artery (Renal, n = 24 during thermal stress, n = 12 during CPTs) or the middle portion of a segmental artery (Segmental, n = 12). RVR was calculated as mean arterial pressure divided by renal or segmental blood velocity. RVR increased at the end of CPT during normothermic baseline in both arteries (Renal: by 1.0 ± 1.0 mmHg·cm-1·s, Segmental: by 2.2 ± 1.2 mmHg·cm-1·s, P ≤ 0.03), and these increases were abolished with passive heating (P ≥ 0.76). At the end of cooling recovery, RVR in both arteries to the CPT was restored to that of normothermic baseline (P ≤ 0.17). These data show that increases in RVR to sympathetic activation during passive heating are attenuated and return to that of normothermic baseline after cooling recovery.NEW & NOTEWORTHY Our data indicate that increases in renal vascular resistance to the cold pressor test (i.e., sympathetic activation) are attenuated during passive heating, but at the end of cooling recovery this response returns to that of normothermic baseline. Importantly, hemodynamic responses were assessed in arteries going to (renal artery) and within (segmental artery) the kidney, which has not been previously examined in the same study during thermal and/or sympathetic stressors.

Age and Gender-Related Changes in Renal Haemodynamics of Albino Rats: The Possible Role of Cytokines and Prostaglandins

AbstractBackground: The normal aging process leads to changes in kidney morphology, hemodynamics and function, which are influenced by several factors, including gender. Females develop less age-dependent loss of renal function due to cardiorenal protective effects of estrogens.Aim of Study: The aim of this study was to elucidate the age and gender-related changes in some renal haemodynamics in albino rats with special focusing on the role of cytokines and prostaglandins in establishment of such changes.Material and Methods: Sixty albino rats (30 males & 30 females) of local strain were divided into 2 major groups (Group I of male rats and Group II of female rats) was further subdivided into 3 subgroups: Young (4wk), young adult (3mo) and old (25mo). Body Weight (BW) and absolute Kidney Weight (KW) were measured. The Systolic Blood Pressure (SBP) of the rats was measured by the rat-tail plethysmography technique using a tail-cuff sphygmomanometer. The Renal Blood Flow Velocity (RBFV) and Renal Vascular Resistance (RVR) were measured using bi-directional blood flow meter with FFT-analysis. The blood samples were collected after a period of overnight fasting, left to be clotted, centrifuged and serum was separated for measurement of serum testosterone in male rats, serum estrogen in female rats, creatinine clearance, serum IL1beta, IL6 and serum PGE.Results: The aging of male rat group is accompanied by change in the renal hemodynamic and some blood measure-ments. This is represented by significant increase in systolic blood pressure, renal vascular resistance, serum PGE, serum interleukin1-b & 6, impaired renal function and significant decrease of renal blood flow. It was observed that the old female group had decreased in estrogen hormone level, which led to increase in systolic blood pressure, renal vascular resistance, serum PGE, serum interleukin1-b & 6 and signif-icant decrease renal blood flow.Conclusion: Aging has a significant influence in renal hemodynamic (decrease of renal blood flow and increase of renal vascular resistance) and also, serum interleukin1-b & 6 have a role in this change accompanied with pathophysiology of aging. Female is more protected from complications of the kidney aging than male due to the previous effect of estrogen hormone.

Extra- And Intra- Renal Vascular Responses To Sympathetic Activation Are Not Modified Following Cooling Recovery

Elevated renal vascular resistance (RVR) during heat stress may provoke localized ischemia, especially when exposed to multiple sympathetic stressors. Whole-body cooling reduces risks associated with heat stress. However, this cooling raises RVR and could therefore exacerbate increases in RVR caused by prior heat stress, particularly during sympathetic activation. PURPOSE: To test hypotheses that increases in both extra- and intra- RVR to the cold pressor test (a sympathoexcitatory stimulus, CPT) are exacerbated by whole-body cooling following heat stress. METHODS: Nineteen healthy adults (22 ± 2 y) underwent passive heat stress sufficient to raise core temperature 1.2°C above normothermic baseline (NT), after which they underwent passive cooling recovery (CR) to within 0.2°C of NT. Participants completed a 2 min CPT at NT and at the end of CR. Changes in body weight provided an indication of dehydration. Heart rate (HR), mean arterial pressure (MAP), and renal blood velocity (RBV) were measured pre-CPT (Pre) and at the end of the CPT (End). RBV was measured using the coronal approach with Doppler ultrasound at the distal segment of the right renal artery (Extra-, n=11) or in the same segmental artery within participants in the right kidney (Intra-, n=8). RVR was calculated as MAP/RBV. Data are presented as mean ± SD. RESULTS: The change in body weight was -1.2 ± 0.5%. In Extra- at Pre, MAP was elevated in CR compared to NT (95 ± 9 vs. 85 ± 7 mmHg, P<0.01) with no differences in HR (58 ± 7 vs 56 ± 9 bpm, P=0.24). MAP and HR in Intra- at Pre did not differ from Extra- (P≥0.72). In Extra- at Pre, RBV (33 ± 4 vs 36 ± 5 cm/s, P=0.01) and RVR (0.35 ± 0.06 vs 0.43 ± 0.08 mmHg/cm/s, P<0.01) were lower in CR compared to NT. RBV was lower and RVR was higher in Intra- compared to Extra- (P<0.02) at Pre. At End, increases in HR (12 ± 9 vs 14 ± 7 bpm, P=0.50) and MAP (24 ± 16 vs 24 ± 16 mmHg, P>0.99) were not different between CR and NT in Extra-. Changes in RBV (-3 ± 5 vs -2 ± 7 cm/s, P=0.59) and increases in RVR (1.24 ± 0.97 vs 0.95 ± 0.99 mmHg/cm/s, P=0.29) did not differ between CR and NT in Extra- at End. There were no differences in the HR, MAP, RBV, or RVR response to CPT in Intra- compared to Extra- (P≥0.10). CONCLUSION: Whole-body cooling following passive heat stress does not affect the extra- or intra- renal vascular responses to sympathetic activation.

Pharmacological inhibition of TRPV4 channels protects against ischemia-reperfusion-induced renal insufficiency in neonatal pigs.

Renal vasoconstriction, an early manifestation of ischemic acute kidney injury (AKI), results in renal hypoperfusion and a rapid decline in kidney function. The pathophysiological mechanisms that underlie ischemia-reperfusion (IR)-induced renal insufficiency are poorly understood, but possibilities include alterations in ion channel-dependent renal vasoregulation. In the present study, we show that pharmacological activation of TRPV4 channels constricted preglomerular microvessels and elicited renal hypoperfusion in neonatal pigs. Bilateral renal ischemia followed by short-term reperfusion increased TRPV4 protein expression in resistance size renal vessels and TRPV4-dependent cation currents in renal vascular smooth muscle cells (SMCs). Selective TRPV4 channel blockers attenuated IR-induced reduction in total renal blood flow (RBF), cortical perfusion, and glomerular filtration rate (GFR). TRPV4 inhibition also diminished renal IR-induced increase in AKI biomarkers. Furthermore, the level of angiotensin II (Ang II) was higher in the urine of IR- compared with sham-operated neonatal pigs. IR did not alter renal vascular expression of Ang II type 1 (AT1) receptors. However, losartan, a selective AT1 receptor antagonist, ameliorated IR-induced renal insufficiency in the pigs. Blockade of TRPV4 channels attenuated Ang II-evoked receptor-operated Ca2+ entry and constriction in preglomerular microvessels. TRPV4 inhibition also blunted Ang II-induced increase in renal vascular resistance (RVR) and hypoperfusion in the pigs. Together, our data suggest that SMC TRPV4-mediated renal vasoconstriction and the ensuing increase in RVR contribute to early hypoperfusion and renal insufficiency elicited by renal IR in neonatal pigs. We propose that multimodal signaling by renal vascular SMC TRPV4 channels controls neonatal renal microcirculation in health and disease.

Renal Hemodynamics During Sympathetic Activation Following Aerobic and Anaerobic Exercise.

We tested the hypotheses that prior aerobic (Study 1) or anaerobic (Study 2) exercise attenuates the increase in renal vascular resistance (RVR) during sympathetic stimulation. Ten healthy young adults (5 females) participated in both Study 1 (aerobic exercise) and Study 2 (anaerobic exercise). In Study 1, subjects completed three minutes of face cooling pre- and post- 30 min of moderate intensity aerobic exercise (68 ± 1% estimate maximal heart rate). In Study 2, subjects completed two minutes of the cold pressor test pre- and post- the completion of a 30 s maximal effort cycling test (Wingate Anaerobic Test). Both face cooling and the cold pressor test stimulate the sympathetic nervous system and elevate RVR. The primary dependent variable in both Studies was renal blood velocity, which was measured at baseline and every minute during sympathetic stimulation. Renal blood velocity was measured via the coronal approach at the distal segment of the right renal artery with pulsed wave Doppler ultrasound. RVR was calculated from the quotient of mean arterial pressure and renal blood velocity. In Study 1, renal blood velocity and RVR did not differ between pre- and post- aerobic exercise (P ≥ 0.24). Face cooling decreased renal blood velocity (P < 0.01) and the magnitude of this decrease did not differ between pre- and post- aerobic exercise (P = 0.52). RVR increased with face cooling (P < 0.01) and the extent of these increases did not differ between pre- and post- aerobic exercise (P = 0.74). In Study 2, renal blood velocity was 2 ± 2 cm/s lower post- anaerobic exercise (P = 0.02), but RVR did not differ (P = 0.08). The cold pressor test decreased renal blood velocity (P < 0.01) and the magnitude of this decrease did not differ between pre- and post- anaerobic exercise (P = 0.26). RVR increased with the cold pressor test (P < 0.01) and the extent of these increases did not differ between pre- and post- anaerobic exercise (P = 0.12). These data indicate that 30 min of moderate intensity aerobic exercise or 30 s of maximal effort anaerobic exercise does not affect the capacity to increase RVR during sympathetic stimulation following exercise.

Renal Hemodynamic Function at the Extremes of T1D Duration-Adolescents vs. Adults with T1D for =50 Years

Our aim was to better understand kidney function changes and RAAS activation over the natural history of T1D in patients with a wide range of T1D duration. GFRinulin and ERPFPAH were measured during a euglycemic clamp before and after an angiotensin II infusion (ANGII, 3 ng·kg-1·min-1-a measure of RAAS activation) in patients with T1D: 28 adolescents (age 16.2±2.0 years), 54 young adults (25.4±5.6 years) and 66 adults with ≥50 years of T1D (65.7±7.5 years) from the Canadian Study of Longevity. Gomez’s equations were used to estimate afferent (RA) and efferent (RE) arteriolar resistances and glomerular hydrostatic pressure (PGLO). In a step-wise fashion, GFRinulin, ERPFPAH, PGLO decreased, renal vascular resistance (RVR) and RA increased in adolescents vs. young adults vs. adults with ≥50 years of T1D (Figure 1). RE was similar in adolescents vs. young adults, but was higher in patients with ≥50 years of T1D. ANGII resulted in blunted renal hemodynamic responses in patients with ≥50 years of T1D (RVR increase of 0.033±0.016 vs. 0.049±0.019mmHg/L/min in adolescents, p=0.0006) suggesting a state of enhanced RAAS activation. With longer duration of disease, patients with T1D have evidence of renal vasoconstriction, leading to lower GFRinulin, ERPFPAH, elevated RVR and RAAS activation. Further work is required to understand the potential role of non-RAAS, pharmacologic agents that target RA in patients with early T1D. Disclosure Y. Lytvyn: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp &amp; Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. M. Farooqi: None. V.S. Lai: None. J.M. Tse: None. L. Cham: None. L. Lovblom: None. A. Weisman: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. E.B. Sochett: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck &amp; Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..