Renal Vascular Resistance Research Articles

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

Phosphodiesterase-5 inhibitor sildenafil attenuates kidney injury induced by Bothrops alternatus snake venom

Acute kidney injury pathogenesis in envenoming by snakes is multifactorial and involves immunologic reactions, hemodynamic disturbances, and direct nephrotoxicity. Sildenafil (SFC), a phosphodiesterase 5 inhibitor, has been reported to protect against pathological kidney changes. ObjectiveThis study aimed to investigate the protective effect of sildenafil against Bothrops alternatus snake venom (BaV)-induced nephrotoxicity. MethodsKidneys from Wistar rats (n = 6, weighing 260–300 g) were isolated and divided into four groups: (1) perfused with a modified Krebs-Henseleit solution (MKHS) containing 6 g% of bovine serum albumin; (2) administered 3 μg/mL SFC; (3) perfused with 3 μg/mL BaV; and (4) administered SFC + BaV, both at 3 μg/mL. Subsequently, the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and percentage of electrolyte tubular sodium and chloride transport (%TNa+, %TCl−, respectively) were evaluated. The cyclic guanosine monophosphate (cGMP) levels were analyzed in the perfusate, and the kidneys were removed to perform oxidative stress and histopathological analyses. ResultsAll renal parameters evaluated were reduced with BaV. In the SFC + BaV group, SFC restored PP to normal values and promoted a significant increase in %TNa+ and %TCl−. cGMP levels were increased in the SFC + BaV group. The oxidative stress biomarkers, malondialdehyde (MDA) and glutathione (GSH), were reduced by BaV. In the SFC + BaV group, a decrease in MDA without an increase in GSH was observed. These findings were confirmed by histological analysis, which showed improvement mainly in tubulis. ConclusionOur data suggest the involvement of phosphodiesterase-5 and cGMP in BaV-induced nephrotoxicity since its effects were attenuated by the administration of SFC.

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine

BackgroundType 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail.MethodsPatients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model.ResultsTreatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups.ConclusionsIn patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects.Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016

Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Profiles in Patients With Heart Failure

Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only. A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.

Abstract P247: Elastin Insufficiency Impairs Renal Hemodynamics And Accelerates Aging-associated Structural And Functional Remodeling Of Preglomerular Arterioles

Elastin degradation and fragmentation are hallmarks of arterial stiffness and renal dysfunction associated with aging. However, it is unclear whether elastin insufficiency contributes to the changes in the structure and function of the resistance vasculature of the kidney during aging. Here we determined how increased vascular stiffness due to elastin insufficiency alters renal hemodynamics and mechanical properties of preglomerular arterioles. We assessed renal hemodynamics under anesthesia in 14-16-month-old female wild type (WT) and elastin heterozygous ( Eln +/- ) mice. Renal autoregulation was assessed by a stepwise increase in renal perfusion pressure (RPP) by simultaneously occluding the superior mesenteric and celiac arteries. Myogenic constriction and arterial stiffness were assessed by pressure myography of isolated renal interlobar arteries. Baseline renal vascular resistance (RVR) was elevated in Eln +/- mice (13.8 ± 2.9 vs 11.2 ± 1.4 mmHg/μL/min/g left kidney weight), while systolic blood pressure (SBP; 75.1 ± 7.4 vs 91 ± 4.2mmHg), renal blood flow (RBF; 6.3 ± 1.2 vs 7.4 ± 1.7 μL/min/g left kidney weight), renal plasma flow (RPF; 3.4 ± 0.8 vs 5 ± 1.2 mL/min/g/ left kidney weight) and urine flow rate, all trended lower in Eln +/- mice compared to WT mice. Glomerular filtration rate (GFR) and filtration fraction (FF) were similar between the two groups. A stepwise increase in RPP caused a slower decline and rise in RBF and RVR, respectively, in Eln +/- relative to WT mice. The maximal changes in RBF (5 ± 1.1 vs 4.7 ± 0.8 μL/min/g left kidney weight), RVR (17.6 ± 7.3 vs 22.5 ± 2.1 mmHg/μL/min/g left kidney weight), urine flow rate,GFR, and FF were less robust in Eln +/- mice. RPF decreased in WT mice in response to raising RPP, whereas it remained unchanged in Eln +/- mice. Myogenic response and increases in elastic modulus and wall tension following stepwise changes in intraluminal pressure were all augmented in interlobar arteries from Eln +/- relative to WT mice. However, there was no difference in kidney weight/tibia length ratio between the two genotypes. We conclude that elastin insufficiency impairs renal hemodynamics by exacerbating age associated increase in vascular stiffness.

Abstract 31: Esomeprazole Improves Blood Pressure, Intrauterine Growth, Inflammation, And Vascular Function During Placental Ischemia Through Inhibition Of NLRP3

Preeclampsia (PE), a multisystem hypertensive disorder of pregnancy is characterized by intrauterine growth restriction (IUGR), inflammation, and vascular dysfunction. NLRP3 inflammasome is a cytoplasmic complex that mediates inflammation and is implicated in CVD. Clinical studies show an association between PE and increased placental NLRP3 expression. We hypothesized that inhibition of NLRP3 using (1) a specific NLRP3 small molecule inhibitor, MCC950 (M9, 20 mg/kg/d, i.p.) or (2) esomeprazole (ESO, 3.5 mg/kg/d, oral), a therapeutic that is safe in pregnancy, would improve MAP, inflammation, IUGR, and vascular dysfunction in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia. Sham (S) or RUPP surgery was performed in pregnant Sprague Dawley rats on gestation day (GD) 14. A subset of rats from both groups received either vehicle, M9, or ESO on GD14-19 (n=9/group). On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound. MAP, fetal, and placental weight were measured, and blood and tissues were processed for additional analyses on GD19. MAP (mmHg) was elevated in RUPP (133±1) vs S (108±2; p&lt;0.05). Treatment with M9 or ESO in RUPP decreased MAP (111±1 and 115±3, respectively; p&lt;0.05 vs RUPP). Fetal weight (g) was reduced in RUPP (2.1±0.04) vs S (2.4±0.05), and ESO normalized fetal weight (2.4±0.01; p&lt;0.05 vs RUPP). Placental NLRP3 mRNA expression increased 5-fold in RUPP vs S (p&lt;0.05); and was less than 2 fold in M9 and ESO treated RUPP rats (p&lt;0.05 vs RUPP). Inflammatory T-helper 17 and cytolytic NK cells, evaluated by flow cytometry, were increased in the circulation, placenta, and kidney of RUPP vs S controls. Treatment with M9 or ESO normalized both cell populations in all tissues (p&lt;0.05 vs RUPP). UARI was increased in RUPP (0.71±0.03) versus S (0.56±0.01; p&lt;0.05) and was decreased to 0.48±0.01 in M9 and 0.61±0.03 in ESO-treated RUPPs (p&lt;0.05 vs RUPP). Renal vascular resistance (mmHg/mL/min/g) was increased in RUPP (42±8) vs S (23±4, p&lt;0.05) and was normalized to 26±3 after treatment with M9 (p&lt;0.05 vs RUPP). These data implicate NLRP3 in mediating inflammation and vascular dysfunction to cause maternal HTN and IUGR in RUPP; and identify NLRP3 as a potential target and ESO as a potential therapeutic for PE.

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.

Reinvestigation of the tonic natriuretic action of intrarenal dopamine: comparison of two variants of salt-dependent hypertension and spontaneously hypertensive rats.

The intrarenal dopamine system has been thoroughly investigated at all levels, especially its role in salt-dependent and other forms of hypertension. However, the evidence regarding dopamine's tonic influence on renal tubular transport of sodium remains equivocal. We reinvestigated its tonic influence on sodium excretion and systemic and renal haemodynamics. Early effects of dopamine D1 receptor blockade using 90-min Schering 23390 (SCH) infusion were examined in anaesthetized rats on 7days' high salt diet (HS), early uninephrectomized rats on 14days' HS diet, drinking 1% saline (HS/UNX), and in spontaneously hypertensive rats (SHR). In the HS group (baseline BP ~133mmHg) renal intracortical SCH promptly decreased sodium, water and total solute excretion (UNa V, V, Uosm V), with significant difference from the solvent-infused group. BP and renal artery blood flow (RBF, Transonic probe) did not change. In HS/UNX model (baseline BP ~150mmHg), characterized by hypertrophy of the remaining kidney, the excretion parameters only tended to decrease whereas SCH induced an ~20% fall in RBF. In SHR (BP ~180mmHg), UNa V and V tended to increase in solvent-infused rats; this increasing tendency was abolished by SCH infusion. During experiments the renal vascular resistance increased significantly in SCH- and solvent-infused SHR. Despite some contradictory findings regarding the genuine tonic control of renal excretion by intrarenal dopamine, our results clearly support such role in rats on HS diet and in SHR, the model resembling human essential hypertension. The observations strengthen the experimental basis and the rationale for targeting the intrarenal dopamine system in attempts to combat arterial hypertension.

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.

Effects of levosimendan on renal blood flow and glomerular filtration in patients with acute kidney injury after cardiac surgery: a double blind, randomized placebo-controlled study

BackgroundAcute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support.MethodsIn this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO2) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70–80 mmHg. Intra-group differences were tested by Mann–Whitney U-tests, and a linear mixed model was used to test time and group interaction.ResultsTwenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m2, p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (− 18% vs. − 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012).ConclusionsIn hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation.Trial registrationNCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1

Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs.

Angiotensin II (ANG II) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma ANG II levels and is associated with increased risk of acute kidney injury. We hypothesized that ANG II antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared, and randomized to intravenous losartan (1.5 mg·kg-1·h-1, n = 8) or an equal volume of intravenous Ringer acetate (vehicle-treated, n = 8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial pressure of <50 mmHg for 30 min. Plasma ANG II levels, hemodynamics and oxygenation were assessed 60 min prehemorrhage, 30-min after the start of hemorrhage, and 60 min posthemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma ANG II levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, ANG II antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.

Skin microvascular function and renal hemodynamics in overweight patients with type 2 diabetes: A cross-sectional study.

ObjectiveDiabetic kidney disease is a microvascular complication of diabetes. Here, we assessed the association between skin microvascular function and renal hemodynamic function in a cohort of well‐phenotyped adults with type 2 diabetes (T2D).MethodsWe included 81 overweight/obese adults (age: 62 ± 8 years; BMI: 32 ± 4 kg/m2) with well‐controlled T2D and no renal impairment. Skin microvascular function was assessed by nailfold capillary density in rest and after arterial occlusion (ie, peak capillary density). Renal hemodynamic functions (ie, measured glomerular filtration rate [mGFR], effective renal blood flow [ERBF], filtration fraction [FF], and effective renal vascular resistance [ERVR]) were assessed by combined inulin and para‐aminohippurate clearances and blood pressure measurements.ResultsSkin capillary density was 45 ± 10 capillaries/mm2 at baseline and 57 ± 11 capillaries/mm2 during post‐occlusive peak; mGFR averaged 108 ± 20 ml/min. In multivariable regression analyses, positive associations between capillary density during post‐occlusive peak and mGFR (β = 0.224; p = 0.022) and ERBF (β = 0.203; p = 0.020) and a positive trend for hyperemia and mGFR (β = 0.391; p = 0.053) were observed, while a negative association for post‐occlusive capillary density with ERVR (β = −0.196; p = 0.027) was found.ConclusionThese findings indicate that microvascular dysfunction in overweight adults with T2D is associated with lower mGFR and ERPF and higher ERVR. We hypothesize that increased renal vascular resistance may contribute to glomerular dysfunction due to impaired renal perfusion.

NLRP3 Plays a Causative Role in Vascular and Renal Dysfunction and Hypertension in Placental Ischemic Pregnancy

Preeclampsia is a multi-system disorder of pregnancy characterized by hypertension (HTN), intrauterine growth restriction (IUGR), organ dysfunction, and inflammation. The NLRP3 inflammasome is a multi-protein complex that initiates the inflammatory response, and has been implicated in chronic kidney disease, AKI, and heart failure. The purpose of the present study was to determine if NLRP3 activation plays a causative role in preeclampsia pathophysiology. We hypothesized that inhibition of NLRP3 activation would attenuate hypertension and IUGR in response to placental ischemia. Pregnant Sprague Dawley rats underwent Sham or Reduced Uterine Perfusion Pressure (RUPP; model of preeclampsia) procedure on Gestation Day (GD) 14. A subset of Sham and RUPP rats received i.p. injections of the specific NLRP3 inhibitor MCC950 (20mg/kg/day) from GD14-GD19. On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound. On GD19, mean arterial pressure (MAP), mean fetal and placental weight were measured, and blood and tissues were processed for additional analysis. MAP (mmHg) was significantly elevated in RUPP (130±1, n=8) compared to Sham (105±1, n=8; p<0.05). Treatment with MCC950 decreased MAP in RUPP+MCC950 (113±2, n=8; p<0.05 vs RUPP). Fetal and placental weights were significantly reduced in RUPP compared to Sham, and treatment with MCC950 had no effect. UARI was significantly increased in RUPP versus Sham (0.70±0.03 vs. 0.56±0.01, respectively; p<0.05) and was normalized to 0.52±0.03 in RUPP+ MCC950. T-helper 17 cells (TH17s) and cytolytic NK cells (cNKs) in the circulation, placenta, and kidney were evaluated by flow cytometry. Circulating TH17s (% gated) were significantly increased in RUPP (2.1±1) vs Sham (0.5±0.2; p<0.05 vs RUPP). Inhibition of NLRP3 significantly reduced circulating TH17s in RUPP+MCC950 (0.4±0.1; p<0.05 vs RUPP). Similar trends were also observed in TH17 populations in placentas and kidneys from each group. Circulating cNKs (% gated) increased from 2.3±0.3 in Sham to 6.4±0.8 in RUPP (p<0.05), and was significantly reduced to 2.3±0.6 in RUPP+MCC950 (p<0.05 vs RUPP). In a separate set of animals, renal function studies were performed to study the impact of MCC950 treatment on renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular resistance (RVR) in all groups. RBF (mL/min/g) was markedly reduced in RUPP (n=4) compared to Sham (n=5) (4±1 vs. 7±1, respectively). Importantly, treatment with MCC950 normalized RBF in RUPP+MCC950 (8±3, n=3) while having no effect in Sham (9±2, n=3). GFR (μL/min/g) was reduced from 1320±177 in Sham and 1117±240 in Sham+MCC950 to 829±124 in RUPP and remained low at 744±180 in RUPP+MCC950. RVR (mmHg/mL/min/g) was markedly increased in RUPP compared to values measured in Sham (42±8 vs. 23±4, respectively) and was normalized to 26±3 in RUPP after treatment with MCC950. The results of this study implicate NLRP3 in directly mediating inflammation, immune cell activation, vascular and renal dysfunction to cause maternal HTN in RUPP. These data suggest that NLRP3 is a potential therapeutic target for treatment in PE.

Sequential Afferent‐Targeted and Total Renal Denervation and Impact on Regulation of Arterial Pressure, Glomerular Filtration, and Sodium Handling in Sprague Dawley Male Rats

Renal denervation (RDNx) is often reported to chronically decrease mean arterial pressure (MAP) in conscious, unchallenged Sprague Dawley (SD) rats, but has no effect of salt-sensitivity of MAP. Although these findings indicate an important role of renal nerves in long-term regulation of MAP under unchallenged conditions, the individual contributions of sympathetic and afferent renal nerves in MAP and renal homeostasis remain unclear. The present study was conducted to test the hypothesis that efferent (sympathetic) renal nerves are the primary contributors both MAP and renal function responses to RDNx in normotensive Sprague Dawley rats. To test this hypothesis, 12 adult male Sprague Dawley rats (300-325g) were subjected to sequential denervation procedures to ablate afferent and efferent nerves separately by subjecting rats to the following surgical sequence: Sham, then afferent-targeted RDNx (A-RDNx), then complete (T)-RDNx. A-RDNx was achieved by periaxonal application of 33mM capsaicin, and T-RDNx was achieved by surgical dissection followed by perivascular application of 10%(v/v) phenol in ethanol. One week was permitted for recovery from surgery before cardiovascular and renal measurements were collected. 24-hour mean arterial pressure (MAP) was recorded by implanted telemetry. Glomerular filtration rate (GFR) was assessed in unrestrained, conscious rats by acute FITC-sinistrin clearance. Renal excretory function was assessed by measuring the urinary sodium excretion response to an acute saline challenge (150mM PBS, 10% bodyweight, i.p.) over four hours. Data was analyzed by one-way repeated-measures ANOVA with Bonferroni post-hoc test (α=0.05). Data presented as mean±SEM. Sham surgery had no significant effect on MAP, GFR or Na Clearance. Following A-RDN treatment, MAP increased ∆5.4±0.9mmHg; (p<0.01); however, no significant changes in GFR or the excretory response to acute sodium load were detected. In contrast, following T-RDN, MAP was decreased 4.9±0.9mmHg (p<.01) following T-RDN vs. compared to A-RDN. Regarding renal function, GFR increased (1.20±0.05 vs. 1.06±0.04 mL/min/100gBWT; p<.01) as did the sodium excretory response to a saline load (28.2±2.3 vs. 18.6±1.0% Na load excreted per 4 hours; p<.01). Together, these data partly support our hypothesis and solidify the role for renal efferent (sympathetic) nerves contribute to long-term regulation of MAP, GFR, and sodium handling in the conscious SD rat. Contrary to our hypothesis, A-RDNx resulted in a small, yet significant, increase in MAP; however, no impact on renal function was observed. We speculate that the increased GFR and decrease in MAP are likely due to a decrease in renal vascular resistance and dilation of the renal afferent arterioles. Moreover, renal afferent nerves appear to contribute to maintenance of MAP in Sprague Dawley rats, which we speculate is through a tonic sympatho-inhibition due to the increase MAP following A-RDNx. These data highlight the important, yet differential roles of efferent and afferent renal nerves, and further studies are underway to further test this hypothesis.

Mas Receptor Blockade Promotes Renal Vascular Response to Ang II after Partial Kidney Ischemia/Reperfusion in a Two-Kidney-One-Clip Hypertensive Rats Model.

Background Partial kidney ischemia-reperfusion (IR) injury is the principal cause of acute kidney injury. The renin-angiotensin system (RAS) and hypertension also may be influenced by renal IR injury. In two models of partial renal IR with and without ischemia preconditioning (IPC) and using Mas receptor (MasR) blockade, A779 or its vehicle, the renal vascular responses to angiotensin II (Ang II) administration in two-kidney-one-clip (2K1C) hypertensive rats were determined. Methods Thirty-seven 2K1C male Wistar rats with systolic blood pressure ≥150 mmHg were randomly divided into three groups; sham, IR, and IPC + IR. The animals in the sham group underwent surgical procedures except partial IR. The rats in the IR group underwent 45 min partial kidney ischemia, and the animals in the IPC + IR group underwent two 5 min cycles of partial kidney ischemia followed by 10 min reperfusion and partial kidney ischemia for 45 min. The renal vascular responses to graded Ang II (30, 100, 300, and 1000 ng kg−1.min−1) infusion using A779 or its vehicle were measured at constant renal perfusion pressure. Results Four weeks after 2K1C implementation, the intravenous infusion of graded Ang II resulted in dose-related increases in mean arterial pressure (MAP) (Pdose < 0.0001) that was not different significantly between the groups. No significant differences were detected between the groups in renal blood flow (RBF) or renal vascular resistance (RVR) responses to Ang II infusion when MasR was not blocked. However, by MasR blockade, these responses were increased in IR and IPC + IR groups that were significantly different from the sham group (P < 0.05). For example, infusion of Ang II at dose 1000 ng kg−1.min−1 resulted in decreased RBF percentage change (RBF%) from the baseline to 17.5 ± 1.9%, 39.7 ± 3.8%, and 31.0 ± 3.4% in sham, IR, and IPC + IR, respectively. Conclusion These data revealed the important role of MasR after partial kidney IR in the responses of RBF and RVR to Ang II administration in 2K1C hypertensive rats.

RELATION BETWEEN NOISE ANNOYANCE, STRESS HORMONES AND THE RENAL HEMODYNAMIC

Objective: Our previous studies showed that healthy men subjectively annoyed by every day noise showed lower renal plasma flow and higher renal vascular resistance compared to not annoyed men. We now further explored the pathophysiological mechanisms of this finding by analysing relations between noise annoyance and chronic stress hormones in healthy men. Design and method: We analysed the renal hemodynamic in 80 healthy men using steady state input clearance with infusion of paraaminohippuric acid and inulin, respectively. Intraglomerular pressure and resistances of the afferent (RA) and efferent (RE) arterioles were calculated according to the Gomez equation. Fasting morning cortisol and dehydroepiandrosterone sultate (DHEA-S) were also measured. All study participants ranked subjective annoyance due to noise in everyday life on a 7 grade likert scale. The median of all rankings was used as cut off point to divide the group into annoyed and non-annoyed subjects. Results: Even though annoyed subjects (n = 32) showed lower renal plasma flow (635 ± 96 vs 685 ± 116 ml/min, p = 0.039) and higher renal vascular resistance (77.4 ± 15 vs 70.0 ± 14 (mmHg/(ml/min)), p = 0.033) compared to not-annoyed subjects (n = 46) there was no difference in serum cortisol and DHEA-S between the groups (table 1). However, there was a correlation between serum cortisol and glomerular filtration rate (r = 0.345, p = 0.002) as well as renal plasma flow (r = 0.408, p &lt; 0.001), and an inverse correlation between serum cortisol and renal vascular resistance (r = -0.420, p &lt; 0.001), resistance of the vas afferens (r = -0.376, p = 0.001) and resistance of the vas efferens (r = -0.441, p &lt; 0.001) in the total healthy study population. There was also an inverse correlation between DHEA-S and resistance of the vas efferens (r = -0.409, p &lt; 0.001) in the total healthy study population. Conclusions: Annoyance due to noise in everyday life was not associated with an increased level of chronic stress hormones. However, our data suggests a relation between chronic stress hormones and impaired renal function. Chronic stress may trigger early renal vascular changes potentially leading to hypertension.

ANNOYANCE DUE TO NOISE TRIGGERS VASCULAR CHANGES IN THE RENAL HEMODYNAMIC

Objective: There is evidence from epidemiological and animal studies that noise exposure is associated with an increased incidence of arterial hypertension and cardiovascular disease. We recently investigated the influence of annoyance due to noise on the renal hemodynamic and found a lower renal plasma flow in patients subjectively annoyed in every-day life compared to not-annoyed patients. We now further explored the pathophysiological mechanisms of this finding. Design and method: We analysed the influence of annoyance due to noise on the renal and systemic hemodynamic in 110 subjects, who were either healthy or presented with drug-naive hypertension (HT) without evidence of end-organ damage. Renal hemodynamic was measured using steady state input clearance with infusion of paraaminohippuric acid and inulin, respectively. Intraglomerular pressure and resistances of the afferent (RA) and efferent (RE) arterioles were calculated according to the Gomez equation. The systemic hemodynamic was recorded by the SphygmoCor System (AtCor Medical). All subjects ranked subjective annoyance due to noise in everyday life on a 7 grade likert scale. The median of all rankings was used as cut off point to divide the group into annoyed and non-annoyed subjects. Results: Annoyed subjects (n = 55) showed lower renal plasma flow (596 ± 108 vs 646 ± 130 ml/min, p = 0.030), higher filtraction fraction (22.9 ± 3.3 vs 21.6 ± 3.2, p = 0.036), higher renal vascular resistance (93.4 ± 27.5 vs 81.0 ± 25.7 mmHg/(ml/min), p = 0.021), higher RA (4565 ± 1744 vs 3792 ± 1676, p = 0.024) and a trend to higher RE (2442 ± 480 vs 2288 ± 411, p = 0.076) compared to not-annoyed subjects (n = 55). There was no difference in glomerular filtration rate (133 ± 12 vs 136 ± 15 ml/min, p = 0.307) and intraglomerular pressure (37.1 ± 2.5 vs 37.6 ± 3.1 mmHg, p = 0.325) between annoyed and not-annoyed subjects. There was also no difference in office blood pressure (133 ± 13/79 ± 10 vs 131 ± 13/78 ± 11 mmHg, p = 0.429/p = 0.527), central blood pressure (115 ± 13/79 ± 11 vs 112 ± 12.8/75 ± 12 mmHg, p = 0.317/p = 0.092), central pulse pressure (36.3 ± 6.9 vs 37.6 ± 6.3 mmHg, p = 0.304) and heart rate (66 ± 8.4 vs 65 ± 10 bpm, p = 0.680) between annoyed and not-annoyed subjects. Conclusions: Annoyance due to noise in everyday life was associated with a vasoconstrictive response in the renal hemodynamic. Our data suggest the hypothesis that annoyance due to noise may trigger early renal vascular changes potentially leading to hypertension.

Long‐Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension and Renal and Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats

BackgroundThe long‐term effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure and cardiovascular and renal health remain controversial. Herein, we investigated the extended (>182 days) effects of DPP4 inhibition in a model of spontaneous hypertension, heart failure, diabetes mellitus, obesity and hyperlipidemia.Methods and ResultsAdult obese spontaneously hypertensive heart failure rats (SHHF) were implanted with radio transmitters for measurement of arterial blood pressures. Two weeks later, SHHF were randomized to receive either a DPP4 inhibitor (sitagliptin, 80 mg/kg per day in drinking water) or placebo. At the end of the radiotelemetry measurements, renal and cardiac function and histology, as well as other relevant biochemical parameters, were assessed. For the first 25 days, mean arterial blood pressures were similar in sitagliptin‐treated versus control SHHF; afterwards, mean arterial blood pressures increased more in sitagliptin‐treated SHHF (P<0.000001). The time‐averaged mean arterial blood pressures from day 26 through 182 were 7.2 mm Hg higher in sitagliptin‐treated SHHF. Similar changes were observed for systolic (8.6 mm Hg) and diastolic (6.1 mm Hg) blood pressures, and sitagliptin augmented hypertension throughout the light‐dark cycle. Long‐term sitagliptin treatment also increased kidney weights, renal vascular resistances, the excretion of kidney injury molecule‐1 (indicates injury to proximal tubules), renal interstitial fibrosis, glomerulosclerosis, renal vascular hypertrophy, left ventricular dysfunction, right ventricular degeneration, and the ratios of collagen IV/collagen III and collagen IV/laminin in the right ventricle.ConclusionsThese findings indicate that, in some genetic backgrounds, long‐term DPP4 inhibitor treatment is harmful and identify an animal model to study mechanisms of, and test ways to prevent, DPP4 inhibitor–induced pathological conditions.

Renal Vascular Response to Angiotensin II Administration in Two Kidneys-One Clip Hypertensive Rats Treated with High Dose of Estradiol: The Role of Mas Receptor.

Backgrounds High blood pressure is one of the most important causes of death around the world. The renin-angiotensin system (RAS) and estradiol are two important items that regulate arterial blood pressure in women. However, hypertension, RAS, and sex hormone estradiol may influence renal vascular responses. This study was designed to determine the role of Mas receptor (MasR) on renal vascular response to angiotensin II (Ang II) administration in two kidneys-one clip (2K1C) hypertensive rats treated with estradiol. Method The ovariectomized rats were subjected to 2K1C or non-2K1C and simultaneously treated with estradiol (500 μg/kg/weekly) or placebo for a period of 4 weeks. Subsequently, under anesthesia, renal vascular responses to graded doses of Ang II administration with MasR blockade (A779) or its vehicle were determined. Results A779 or its vehicle did not alter mean arterial pressure (MAP), renal perfusion pressure (RPP), and renal blood flow (RBF). However, in non-2K1C rats, Ang II infusion decreased RBF and increased renal vascular resistance (RVR) responses in a dose-related manner (Ptreat < 0.0001). The greatest responses were found in ovariectomized estradiol-treated rats that received A779 (Pgroup < 0.05) in non-2K1C rats. Such findings were not detected in 2K1C hypertensive rats. For example, in estradiol-treated rats that received A779, at 1000 ng/kg/min of Ang II infusion, RBF reduced from 1.6 ± 0.2 to 0.89 ± 0.19 ml/min in non-2K1C rats, and it reduced from 1.6 ± 0.2 to 1.2 ± 0.2 ml/min in 2K1C rats. Conclusion Hypertension induced by 2K1C may attenuate the role of A779 and estradiol in renal vascular responses to Ang II infusion. Perhaps, this response can be explained by the reduction of Ang II type 1 receptor (AT1R) expression in the 2K1C hypertensive rats.

Sex Differences in the Renal Vascular Responses of AT1 and Mas Receptors in Two-Kidney-One-Clip Hypertension.

Background The prevalence and severity of hypertension, as well as the activity of the systemic and local renin angiotensin systems (RASs), are gender related, with more symptoms in males than in females. However, the underlying mechanisms are not well understood. In this study, we investigated sex differences in renal vascular responses to angiotensin II (Ang II) administration with and without Ang II type 1 and Mas receptor (AT1R and MasR) antagonists (losartan and A779) in the 2K1C rat model of renovascular hypertension. Methods Male and female 2K1C rats were divided into 8 experimental groups (4 of each sex) treated with vehicle, losartan, A779, or A779+losartan. Responses of mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) to Ang II were determined. Results In both sexes, the basal MAP, RBF, and RVR were not significantly different between the four groups during the control period. The Ang II administration decreased RBF and increased RVR in a dose-related manner in both sexes pretreated with vehicle or A779 (Pdose < 0.0001), but in vehicle pretreated groups, RBF and RVR responses were different between male and female rats (Pgroup < 0.05). AT1R blockade increased RBF and decreased RVR responses to Ang II, and no difference between the sexes was detected. Coblockades of AT1R and MasR receptors increased RBF response to Ang II significantly in males alone but not in females (Pgroup=0.04). Conclusion The impact of Ang II on RBF and RVR responses seems to be gender related with a greater effect on males, and this sex difference abolishes by Mas receptor blockade. However, the paradoxical role of dual losartan and A779 may provide the different receptor interaction in RAS between male and female rats.