Endovascular renal denervation reduces blood pressure (BP). We explored an alternative approach to renal denervation using radiofrequency energy delivered across the renal pelvis utilizing the natural orifice of the urethra and the ureters.

Peritubular capillary hydrostatic and oncotic forces and their relationship to the renal excretion of sodium (UNaV) were examined in 19 patients with moderate and uncomplicated essential hypertension (HT) and compared with data from 20 normotensive subjects (NT). Observations were made in hydropenia (C) and during sustained isotonic saline volume expansion (E; 3% increase in body weight). The intrarenal venous pressure (IRVP) was used as an index of peritubular capillary hydrostatic pressure, and the efferent arteriolar colloid osmotic pressure (COPeff) was estimated from the arterial COP and the filtration fraction. C values (mean +/- SEM) in HT (and NT) were: arterial pressure (MAP) 110 +/- 3 mm Hg (85 +/- 1, p less than 0.001); glomerular filtration rate (GFR) 122 +/- 4 ml/min/1.73 m2 (128 +/- 3, p greater than 0.05); renal blood flow (RBF) 1172 +/- 38 ml/min/1.73 m2 (1298 +/- 48, p less than 0.05); IRVP 25.0 +/- 1.0 mm Hg (24.8 +/- 0.8, p greater than 0.05); COPeff 33.0 +/- 0.7 mm Hg (31.9 +/- 0.6, p greater than 0.05); and UNaV 140 +/- 13 mumole/min (161 +/- 12, p greater than 0.05). During E, the increase of UNaV in HT was more than double that of NT (p less than 0.001) while IRVP did not change in either group (p greater than 0.05); and COPeff fell by 26% (p less than 0.001) in both groups. GFR and RBF increased by 18% (p less than 0.001) and 19% (p less than 0.001) respectively, in HT, but did not change in NT. MAP remained unchanged in both groups. The results indicate that the peritubular capillary physical factors are normal in established essential hypertension, and that these forces are not involved in the exaggerated natriuretic response to volume expansion in essential hypertension.

Microinjection of the inhibitory neurotransmitter gamma-aminobutyric acid B-subtype receptor agonist baclofen into the nucleus tractus solitarius increases arterial blood pressure and sympathetic nerve discharge. The baclofen-induced pressor response is enhanced in chronic hypertension. We hypothesized that a postsynaptic mechanism contributes to the enhanced responses to baclofen in hypertension. We investigated the postsynaptic effect of baclofen on second-order baroreceptor neurons, identified by 1,1'-dilinoleyl-3,3,3',3'-tetra-methylindocarbocyanine, 4-chlorobenzenesulphonate labeling of the aortic nerve, in nucleus tractus solitarius slices from sham-operated normotensive and unilateral nephrectomized, renal-wrap hypertensive rats. After 4 weeks, arterial blood pressure was 153+/-7 mm Hg in hypertensive rats (n=9) and 93+/-3 mm Hg in normotensive rats (n=8; P<0.05). There was no difference in resting membrane potential (54.5+/-0.7 versus 53.3+/-0.6 mV) or input resistance (1.07+/-0.11 versus 1.03+/-0.11 GOmega) between hypertensive and normotensive neurons (both n=18). Baclofen induced a net outward current in nucleus tractus solitarius neurons in the presence of 1 micromol/L tetrodotoxin. The EC50 of the baclofen effect was greater in normotensive cells (9.1+/-3.2 micromol/L; n=5) than hypertensive cells (3.0+/-0.5 micromol/L; n=7; P<0.05), and baclofen (10 micromol/L) induced a greater decrease in input resistance in hypertensive cells (61+/-2%; n=6) than in normotensive cells (45+/-4%; n=9; P<0.05). Both potassium and calcium channels were involved in the baclofen-evoked whole-cell current. The results suggest an enhanced postsynaptic response to activation of inhibitory neurotransmitter gamma-aminobutyric acid B-subtype receptors in second-order baroreceptor neurons in the nucleus tractus solitarius in renal-wrap hypertensive rats. This enhanced inhibition could alter baroreflex function in chronic hypertension.

The endogenous purine 8-aminoguanine induces diuresis/natriuresis/glucosuria by inhibiting PNPase (purine nucleoside phosphorylase); however, mechanistic details are unknown.

Ang II (angiotensin II) releases arachidonic acid from tissue phospholipids that is metabolized by 12/15-lipoxygenase (ALOX15), generating 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), which have been implicated in cardiovascular and renal diseases. In this study, we tested the hypothesis that ovariectomy augments Ang II-induced hypertension and renal pathophysiological changes via ALOX15 activation in female mice.

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

[Figure: see text].

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in Gpr81-/- mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81-/- mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SSPer1-/-), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure.

Long noncoding RNAs (lncRNAs) are an emerging class of genomic regulatory molecules reported in various species. In the rat, which is one of the major mammalian model organisms, discovery of lncRNAs on a genome-wide scale is lagging. Renal lncRNA sequencing and lncRNA transcriptome analysis were conducted in 3 rat strains that are widely used in cardiovascular and renal research: the Dahl salt-sensitive rat, the spontaneously hypertensive rat, and the Dahl salt-resistant rat. Through the RNA sequencing approach, 3273 transcripts were identified as rat lncRNAs. A majority of lncRNAs were without predicted target genes. Differential expression of 273 and 749 lncRNAs was detected between Dahl salt-sensitive versus Dahl salt-resistant and Dahl salt-sensitive versus spontaneously hypertensive rat comparisons, respectively. To couple the observed differential expression of lncRNAs with the status of mRNAs, an mRNA transcriptome analysis was conducted. Several cis mRNA genes were coregulated with lncRNAs. Of these, the protein expression status of 4 target genes, Asb3, Chac2, Pex11b, and Sp5, were differentially expressed between the relevant strain comparisons, thereby suggesting that the differentially expressed lncRNAs associated with these genes are candidate genetic determinants of blood pressure. This study serves as a first-generation catalog of rat lncRNAs and illustrates the prioritization of lncRNAs as candidates for complex polygenic traits.

For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight <10th centile (Pinteraction=0.005), but more preterm birth (Pinteraction=0.043), and no effect on perinatal death or high-level neonatal care >48 hours (Pinteraction=0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks (Pinteraction=0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes.

Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2-dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease.

The Global SYMPLICITY Registry DEFINE (Denervation Findings in Real World) investigates radiofrequency renal denervation (RDN) in a broad range of patients with hypertension. We evaluated whether the number or type of antihypertensive medications were associated with increased long-term blood pressure (BP) reductions and cardiovascular outcomes following radiofrequency RDN.

Renal denervation (RDN) lowers blood pressure (BP), but BP response is variable in individual patients. We investigated whether measures of pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, predict BP drop following RDN.

Lack or downregulation of the dopamine D2 receptor (D2R) increases the vulnerability to renal inflammation independent of blood pressure in mice. Common single nucleotide polymorphisms (SNPs) rs6276, 6277, and 1800497 in the human D2R gene are associated with decreased receptor expression/function and hypertension. Human renal proximal tubule cells from subjects carrying these SNPs have decreased D2R expression and increased expression of profibrotic factors and production of extracellular matrix proteins. We tested the hypothesis that the D2R mediates these effects by regulating micro-RNA expression. In cells carrying D2R SNPs, micro-RNAs (miRs)-217, miR-224, miR-335, and miR-1265 were downregulated, whereas miR-1290 was upregulated >4-fold compared with those carrying D2R wild-type alleles. However, only miR-217 was directly regulated by D2R expression. In cells carrying D2R wild-type, miR-217 inhibitor increased the expression of transforming growth factor (TGF)-β1, matrix metalloproteinase 3, fibronectin 1, and collagen 1a, whereas miR-217 mimic had the opposite effect. In cells carrying D2R SNPs, miR-217 mimic also decreased the expression of TGFβ1 and its targets. Wnt5a, a miR-217 target, was increased in cells carrying D2R SNPs and decreased by miR-217 mimic but increased by miR-217 inhibitor in both cell types. In cells carrying D2R wild-type, Wnt5a treatment increased TGFβ1 while silencing Ror2, a Wnt5a receptor, decreased TGFβ1 and blunted the Wnt5a-induced increase in cells carrying D2R wild-type. Our results show that renal proximal tubule cells from subjects carrying D2R SNPs resulting in D2R downregulation have increased TGFβ1 that is mediated by decreased regulation of the miR-217-Wnt5a-Ror2 pathway.

The present study directly tested the crucial role of intestinal gastrin/CCKBR (cholecystokinin B receptor) in the treatment of salt-sensitive hypertension.

Lowering blood pressure (BP) can lead to an initial decline in estimated glomerular filtration rate (eGFR). However, there is debate how much eGFR decline is acceptable. We performed a post hoc analysis of ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial), which randomized patients to intensive or standard systolic BP-targets. We determined the relation between initial decline in mean arterial pressure and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR decline after 1 year. A total of 13 266 patients with 41 126 eGFR measurements were analyzed. Up to 10 mm Hg of BP-lowering, eGFR did not change. Hereafter, there was a linear decrease of 3.4% eGFR (95% CI, 2.9%-3.9%) per 10 mm Hg mean arterial pressure decrease. The observed eGFR decline based on 95% of the subjects varied from 26% after 0 mm Hg to 46% with a 40 mm Hg mean arterial pressure decrease. There was no difference in eGFR slope (P=0.37) according to initial eGFR decline and BP-target, with a decrease of 1.24 (95% CI, 1.09-1.39), 1.20 (95% CI, 0.97-1.43), and 1.14 (95% CI, 0.77-1.50) in the 5%, 5% to 20%, and >20% stratum during intensive and 0.95 (95% CI, 0.81-1.09), 1.23 (95% CI, 0.97-1.49), and 1.17 (95% CI, 0.65-1.69) mL/minute per 1.73 m2 per year during standard treatment. In patients at high cardiovascular risk with and without diabetes mellitus, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. Our results support that an eGFR decrease up to 20% after BP lowering can be accepted and suggest that the limit can be extended up to 46% depending on the achieved BP reduction. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000620, NCT01206062.

We assessed the effect of blood pressure (BP) control on left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH).

[Figure: see text].