Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex dependent programmed hypertension by maternal diabetes

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory, and antioxidant actions, particularly in conditions of elevated HO-1 expression, or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function compared to male. Diabetes was induced in pregnant rats by a single dose of Streptozotocin (STZ, 50mg/kg i.p) in late gestation. Three months old male offspring from diabetic mothers (MOD) exhibited higher blood pressure values (BP), higher renal vascular resistance (RVR), worse endothelium -dependent response to Acetylcholine and an increased constrictor response to Phenylephrine, compared to those in aged matched female (FOD), which were abolished by chronic Tempol (1mM) treatment. In anesthetized animals, Stannous mesoporphyrin (SnMP; 40 µmol/kg i.v.) administration, to inhibit HO activity, increased RVR in FOD and reduced glomerular filtration rate in MOD, without altering these parameters in control animals. Compared to MOD, FOD showed lower nitrotirosyne levels, and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with Tempol to MOD, prevented elevations in nitrotyrosine levels, and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex specific hypertension, and renal alterations associated to oxidative stress, mainly in adult male offspring, which are reduced in the female offspring, by elevation in HO-1 expression and lower oxidative stress levels.

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

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. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Russian Foundation for Basic Research

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

Background Type 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. Methods Patients (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. Results Treatment 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. Conclusions In 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

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.

A STUDY ON THE CORRELATION BETWEEN THE ENDOTHELIN-1, NITRIC OXIDE FUNCTION AND THE RENAL HEMODYNAMICS IN PATIENTS WITH HYPERTENSIVE DISORDERS IN PREGNANCY IN HUBEI

Objective: To analyze the correlation between the vascular endothelial function (characterized by endothelin-1 and nitric oxide) and the renal hemodynamics in patients with hypertensive disorders in pregnancy (HDP) by color Doppler ultrasound. Method: Depending on the severity of the disease, 76 HDP patients were divided into three groups, namely, pregnancy-induced hypertension (PIH) group ([Formula: see text]), mild preeclampsia (PE) group ([Formula: see text]), and severe PE group ([Formula: see text]). In the meantime, 28 healthy pregnant women were selected as controls. Color Doppler ultrasound was performed to determine the following parameters in the interlobar arteries of the kidney: Resistance index (RI), peak end-diastolic velocity (EDV), pulsatility index (PI), peak systolic velocity (PSV), and S/D ratio. The correlations of these parameters with the serum levels of ET-1 and NO were then analyzed. Result: (1) In the interlobar arteries of the kidney, RI, S/D, PI were positively significantly correlated to the serum level of ET-1 in HDP patients (All [Formula: see text]) and negatively to the serum level of NO (All [Formula: see text]). (2) RI, S/D, PI of the mild and severe PE groups were significantly higher than those of the control group (All [Formula: see text]). However, EDV of the mild and severe PE groups was significantly lower than that of the control group (All [Formula: see text]). (3) The serum level of ET-1 was significantly higher in the HDP patients than in the control group ([Formula: see text]). However, the serum level of NO was significantly lower in the former than in the latter ([Formula: see text]). As HDP became more severe, there was an elevation in the serum level of ET-1 and a decrease in NO. Conclusion: Indicators of renal hemodynamics measured by color Doppler ultrasound were correlated to the serum levels of ET-1 and NO characterizing the vascular endothelial function. They were sensitive indicators reflecting hemodynamic changes and renal impairment in HDP patients.

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

Background Diabetes 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. Methods Wistar 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. Results DM 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. Conclusion This 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.

Macula Densa NOS1β Modulates Renal Hemodynamics and Blood Pressure During Pregnancy: Role in Gestational Hypertension

Background: Regulation of renal hemodynamics and blood pressure (BP) via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing glomerular filtration rate (GFR) to increase and BP to decrease. Methods: We employed sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radio-telemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. Results: Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies but decreased in spontaneous gestational hypertensive pregnancies. Conclusions: Macula densa NOS1β plays a critical role in control of renal hemodynamics and BP during pregnancy.