Renal Vasoconstriction Research Articles

Renal Vasoconstrictor, but Not Vasodilator, Responses are Modified by Mild Passive Heat Stress in Humans

Purpose The effect of heat stress on renal vascular control is not well studied. For instance, moderate passive heat stress attenuates the renal segmental artery vasoconstrictor response to the cold pressor test (CPT), a sympathoexcitatory stimulus. Whether this occurs with mild passive heat stress is unknown. Additionally, the vasodilatory response of the kidneys has never been studied during heat stress. Oral protein loading is a common approach used to elicit increases in renal blood flow. The purpose of this study was to test the hypothesis that both renal segmental artery vasoconstriction and vasodilation are attenuated during mild passive heat stress. Methods Twelve healthy adults (26 ± 1 y, 3 females) completed two experimental visits where they underwent passive heat stress or a normothermic time control trial in a randomized crossover design. In the heat stress trial, core temperature was increased ~0.5°C within the first hour and was maintained thereafter. Subjects completed a CPT one hour into heat stress which involved subjects immersing their right hand in an agitated ice slurry for 2 min. One hour post-CPT, subjects ingested a whey protein shake (1.2 g of protein/kg of body weight mixed with water). Renal segmental artery blood velocity (BV, Doppler ultrasound) and beat-to-beat blood pressure (Penaz method) were measured pre-CPT, in the final minute of CPT, pre-protein, and 150 min post-protein. Segmental artery vascular resistance (VR) was calculated as mean arterial pressure (MAP) divided by segmental artery BV. Data are presented as mean ± SD. Results Core temperature was higher pre-CPT (37.6 ± 0.5 vs 37.1 ± 0.5°C, P<0.01) and pre-protein (37.7 ± 0.4 vs 37.0 ± 0.4°C, P<0.01), and body fluid loss was greater (3.0 ± 0.9% vs. 1.5 ± 0.4%, P<0.01) in heat stress compared to normothermia. MAP did not differ pre-CPT between heat stress (80 ± 11 mmHg) and normothermia (84 ± 9 mmHg, P=0.76), but during the CPT was lower during heat stress (88 ± 18 vs. 113 ± 14 mmHg, P<0.01). Segmental BV did not differ pre-CPT between heat stress (22 ± 3 cm/s) and normothermia (22 ± 4 cm/s, P=0.99) or during the CPT (P = 0.56). Segmental VR pre-CPT did not differ between heat stress (3.8 ± 0.6 mmHg/cm/s) and normothermia (4.0 ± 0.7 mmHg/cm/s, P=0.91) but was lower in heat stress during the CPT (5.7 ± 1.1 vs. 4.6 ± 1.5 mmHg/cm/s, P=0.01). MAP did not differ pre-protein between heat stress (83 ± 9 mmHg) and normothermia (85 ± 9 mmHg, P=0.93), or post-protein (P=0.94). Segmental BV did not differ pre-protein between heat stress (22 ± 3 cm/s) and normothermia (22 ± 3 cm/s, P=0.99), or post-protein (P=0.36). Segmental VR was not different pre-protein between heat stress (3.9 ± 0.8 mmHg/cm/s, P=0.97) and normothermia (3.9 ± 0.6 mmHg/cm/s). Segmental VR decreased post-protein (P=0.03) but did not differ between heat stress (3.4 ± 0.9 mmHg/cm/s) and normothermia (3.5 ± 0.5 mmHg/cm/s, P=0.98). Conclusion Compared to normothermia, renal segmental artery vasoconstriction during a sympathetic stimulus is attenuated, but renal segmental artery vasodilation following a protein load is not affected by mild passive heat stress.

Maternal and Fetal Defects of Gestational Angiotensin 1‐7 Receptor Antagonism: A Possible Preclinical Model of Preeclampsia

Preeclampsia (PE) is a complex pathological state associated with serious adverse maternal and fetal consequences. Imbalances of the pressor ACE/Ang II and depressor ACE2/Ang 1-7 arms of renin-angiotensin system are implicated in PE pathophysiology. The current experimental study investigated whether the blockade of Ang 1-7 receptors (Mas receptors) during late pregnancy would replicate clinical features of PE. Two different dosing regimens of A779 (Mas receptor antagonist, 0.750 and 1.3 mg/kg/day s.c.) were administered daily to pregnant rats for 7 consecutive days starting from gestational day 14. The developed maternal and fetal abnormalities were compared to those produced by gestational L-NAME administration (50 mg/kg/day for 7 days), a standard model of PE in rodents. Gestational administration of L-NAME or A779 reduced weight and number of placentas and pups and increased death and resorption percentages of pups. These effects were more evident with the lower dose of A779 than with the higher dose. Moreover, A779 or L-NAME provoked similar elevations in systolic blood pressure and proteinuria. Immunohistochemical studies on placental tissues revealed enhanced protein expression of NFκB in dams treated with L-NAME or the lower, but not higher, dose of A779. While placental ACE expression remained unaltered, ACE2 expression was upregulated by A779 and L-NAME. Studies in isolated perfused kidneys demonstrated diminished acetylcholine vasodilation in L-NAME, but not A779, challenged preparations. Neither drug affected renal vasoconstriction induced by Ang II or phenylephrine. The current data highlight the likelihood of exploiting pregnant dams with pharmacologically eliminated Mas receptors for PE modeling in rodents. However, more studies are needed to further validate the model fidelity and its intimate resemblance to human PE.

Chronic Renal Artery Insulin Infusion Decreases 24 hr/day Renal Blood Flow in Diabetic Rats

The renal effects of type 1 diabetes, e.g. natriuresis and vasodilation, are ascribed directly to the hyperglycemia. We reported that 6 days of diabetes (~ 400 mg/dl) in dogs did not cause sustained natriuresis if plasma insulin was not allowed to decrease below normal. This suggested that the decrease in insulin and loss of its sodium retaining influence, rather than hyperglycemia, was responsible for sustained natriuresis in type 1 diabetes. This study tested the role of the decrease in insulin in mediating the renal blood flow (RBF) response to diabetes. Rats were instrumented with a chronic catheter in the left renal artery, inserted via a puncture in the aorta at the origination of the renal artery. The right kidney was removed, and a Transonic flow probe was placed on the left renal artery. Artery and vein catheters were implanted. The flow probe cable and catheters were exteriorized through a button in the scapular region and rats were placed in metabolic cages. They were connected to a Dragonfly commutator and Instech dual-channel hydraulic swivel mounted in series for continuous, 24 hr/day intravenous (IV) and intrarenal (IR) infusion while measuring RBF continuously, 24 hr/day. In 5 rats, RBF averaged 10.8±1.5 ml/min during baseline and averaged 11.0±0.7 ml/min during 1-4 days of diabetes (STZ, 40 mg/kg). Insulin then was added to the IR saline vehicle at a dose of 0.3 mU/kg/min, which we have reported did not spill over systemically in rats. The next four days of IR insulin infusion yielded decreasing RBF values of 10.9±1.3, 10.2±1.1, 7.9±1.2, and 7.8±1.0 ml/min. RBF did not recover when IR insulin was stopped, so 2 Control rats underwent 7 days of diabetes without IR insulin. Baseline RBF averaged 7.8 ml/min, and over the next 7 days averaged: 8.4, 12.0, 11.9, 10.9, 10.2, 10.6, and 10.7 ml/min. The RI insulin infusion also was tested in one additional rat that was not diabetic. There was no change in RBF or blood glucose over 4 days of infusion. These results suggest a chronic renal vasoconstrictor influence of insulin under diabetic conditions. We hypothesize this suggests that the decrease in insulin may contribute directly to the renal vasodilation that occurs in type 1 diabetes.

Gender differences in the renal changes induced by a prolonged high-fat diet in rats with altered renal development

The mechanisms involved in renal dysfunction induced by high-fat diet (HFD) in subjects with altered renal development (ARDev) are understudied. The objective of this study is to examine whether there are sex-dependent differences in the mechanisms involved in the hypertension and deterioration of renal function in SD rats with prolonged HFD and ARDev. The role of angiotensin II (Ang II) in the arterial pressure (AP) increments, the renal hemodynamic sensitivity to Ang II, glomerular damage and changes in fat abdominal volume, plasma adipokine levels, renal NADPHp67phox expression, and renal infiltration of immune cells were examined. Hypertension and deterioration of renal function were enhanced (P < 0.05) in both sexes of rats with HFD and ARDev. The decrease (P < 0.05) of AP elicited by candesartan in hypertensive rats was similar to that induced by the simultaneous administration of candesartan and apocynin. The greater (P < 0.05) renal vasoconstriction induced by Ang II in both sexes of rats with HFD and ARDev was accompanied by an enhanced (P < 0.05) infiltration of CD-3 cells and macrophages in the renal cortex and renal medulla. The increments (P < 0.05) in the renal expression of NADPHp67phox and glomeruloesclerosis were greater (P < 0.05) in males than in females with HFD and ARDev. Our results suggest that the hypertension and deterioration of renal function induced by HFD in rats with ARDev are Ang II-dependent and mediated by increments in oxidative stress and immune system activation. Sex-dependent increments in oxidative stress and glomerular damage may contribute to the deterioration of renal function in these rats.

English

BACKGROUND The increased propensity for acute kidney injury (AKI) in patients with cirrhosis stems from haemodynamic abnormalities typical for patients with cirrhosis and ascites. 15 which is due to development of portal hypertension and portosystemic collaterals with splanchnic and systemic vasodilatation, resulting in decrease in effective arterial blood volume with increase in renin angiotensin-aldosterone system (RAAS), sympathetic nervous system and non-osmotic release of antidiuretic hormone causing sodium retention, increased intravascular volume, and a hyperdynamic circulatory state, 16 complemented with increased production of nitric oxide which is considered the main cause of vasodilatation in cirrhosis. Mechanism of renal dysfunction in cirrhosis includes portal hypertension &amp; its accompanying haemodynamic abnormalities15 leading to increased synthesis of endogenous vasodilatory compounds such as nitric oxide leading to vasodilatation in splanchnic &amp; systemic arterial systems ultimately leading to activation of reninangiotensinogen–aldosterone system causing compensatory renal vasoconstriction &amp; hypo-perfusion resulting into renal failure. We wanted to study the clinical profile of patients with AKI who presented to a tertiary care hospital in Bangalore. METHODS Ninety-four patients of either gender admitted in the department of gastroenterology at a tertiary care hospital with age &gt; 18 years with either diagnosed or newly diagnosed case of cirrhosis of liver (including both compensated &amp; decompensated cases) admitted with acute kidney injury diagnosed according to International Club of Ascites Classification were enrolled in this study. The sample size was based on number of eligible patients admitted to tertiary care hospital during the study period. Details of the study were explained to them and consent was taken either from the patient or their attender. RESULTS Most patients were in the age group &gt; 60 yrs. with 32 male patients (45.07 %) in the age group of 40 - 60 years &amp; 13 female patients (56.52 %) in the age group of &gt; 60 yrs. 78.7 % of patients developed AKI before hospital admission i.e., at community level; whereas 21.3 % of patients developed AKI after hospital admission i.e., they had normal creatinine level on admission. CONCLUSIONS Pre renal AKI was the most common cause of AKI followed by hepatorenal syndrome &amp; acute tubular necrosis (ATN) comprising 52.1 %, 28.7 % &amp; 19.1 % respectively. KEYWORDS AKI, Cirrhosis, ATN

Causes of development and progression of cardiorenal syndrome in heart failure patients. Prevention methods

The review includes data on the pathogenesis of cardiorenal syndrome (CRS) in patients with heart failure (HF). Renal hypertension has been identified as an important cause of its development and progression. The mechanisms of its formation in patients with low cardiac output are considered. In this setting, renal vasoconstriction, due to neuroendocrine activation, and external parenchymal compression, due to increased intra-abdominal pressure, developed. Both mechanisms were responsible for the decreased glomerular filtration rate. Hypokalemia has often accompanied by CRS. Potassium deficiency aggravated the decrease in cardiac output and provoked arrhythmias. This increased renal hypertension. High doses of furosemide in the treatment of acute decompensated HF sometimes damaged the kidneys due to hypovolemia and hypokalemia. Such side effects of furosemide as a neuroendocrine activation with subsequent vasoconstriction and the development of endothelial dysfunction due to oxidative stress are considered. Two directions of prevention of nephrotoxic effects of the drug are proposed. The proposed prevention methods have shown encouraging results.

Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications.

The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1–D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.

Hepatorenal Sendrom Tanısı Olan Bireylerde Hemşirelik Bakımı

Hepatorenal sendrom, karaciğer yetmezliği olan hastalarda görülen en yaygın komplikasyonlardan biridir. Azotemi, oligüri, glomerüler filtrasyon hızının azalması ve inatçı assitin artmasıyla ortaya çıkan böbrek yetmezliği tablosudur. Böbreklerde yapısal bir sorun yoktur. Hepatorenal sendrom oluşumuna portal hipertansiyon, splenik arteriyel vazodilatasyon sebep olur. Sonuç olarak, renal hipoperfüzyona neden olan renal vazokonstrüksiyon gelişir. Karaciğer transplantasyonu gerçekleşen hastalarda ameliyat sırasındaki yetersiz perfüzyona bağlı gelişen akut tübüler nekroz, ameliyat sonrası hipovolemi ve ilaçlara bağlı gelişen nefrotoksisite, karaciğer nakli sonrası böbrek yetmezliğinin diğer önemli nedenlerindendir. Tedavide amaç, splenik ve sistemik vazokonstrüksiyonun düzeltilmesi, böbreklerin vazodilatasyonunun sağlanması ve sodyum dengesi ile birlikte normovoleminin sağlanmasıdır. Hemşirelik bakımında; klinikte hastanın hemodinamisinin stabil olması sağlanmalı, laboratuvar bulguları izlenmeli ve hastanın durumu sıklıkla değerlendirilmelidir. Ayrıca hasta sıvı-elektrolit dengesizlikleri yönünden izlenmelidir. Hepatorenal sendroma bağlı olarak hastanın saatlik diürez miktarı, ortalama arter basıncı, kreatinin klirensi ve serum kreatin gibi kritik değerlerindeki ani değişimler, su ve tuz tutulumuna bağlı olarak ortaya çıkan ödem hastanın hemodinamisinin olumsuz etkilenmesine neden olur. Özellikle yoğun bakım ünitelerinde hastaların izlemi önem taşımaktadır.

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.

Changes in the renal function after acute mercuric chloride exposure in the rat are associated with renal vascular endothelial dysfunction and proximal tubule NHE3 inhibition

Mercury is an environmental pollutant and a threat to human health. Mercuric chloride (HgCl2)-induced acute renal failure has been described by several reports, but the mechanisms of renal dysfunction remain elusive. This study tested the hypothesis that HgCl2 directly impairs renal vascular reactivity. Additionally, due to the mercury toxicity on the proximal tubule, we investigated whether the HgCl2-induced natriuresis is accompanied by inhibition of Na+/H+ exchanger isoform-3 (NHE3). We found that 90-min HgCl2 infusion (6.5 μg/kg i.v.) remarkably increased urinary output, reduced GFR and renal blood flow, and increased vascular resistance in rats. “In vitro” experiments of HgCl2 infusion in isolated renal vascular bed demonstrated an elevation of perfusion pressure in a concentration- and time-dependent manner, associated with changes on the endothelium-dependent vasodilatation and the flow-pressure relationship. Moreover, by employing “in vivo” stationary microperfusion of the proximal tubule, we found that HgCl2 inhibits NHE3 activity and increases the phosphorylation of NHE3 at serine 552 in the renal cortex, in line with the HgCl2-induced diuresis. Changes in renal proximal tubular function induced by HgCl2 were parallel to increased urinary markers of proximal tubular injury. Besides, atomic spectrometry showed that mercury accumulated in the renal cortex. We conclude that acute HgCl2 exposure causes renal vasoconstriction that is associated with reduced endothelial vasodilator agonist- and flow-mediated responses and inhibition of NHE3-mediated sodium reabsorption. Thus, our data suggest that HgCl2-induced acute renal failure may be attributable at least in part by its direct effects on renal hemodynamics and NHE3 activity.

Knockout of γ-Adducin Promotes NG-Nitro-L-Arginine-Methyl-Ester-Induced Hypertensive Renal Injury.

Previous studies identified a region on chromosome 1 associated with NG-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant γ-adducin (Add3) gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of Add3 impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1Brown Norway (FHH 1BN) congenic rats (WT) expressing wild-type Add3 gene versus FHH 1BN Add3 KO rats. RBF was well autoregulated in WT rats but impaired in Add3 KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in Add3 KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in Add3 KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME-treated Add3 KO rats than in WT rats. Hypertensive Add3 KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME-induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT: A mutation in the γ-adducin (Add3) gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced NG-nitro-L-arginine methyl ester-induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.

15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury

The two primary mechanisms by which iodinated contrast media (CM) causes contrast-induced acute kidney injury (CIAKI) are the hemodynamic effect causing intrarenal vasoconstriction and the tubular toxic effect causing acute tubular necrosis. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades prostaglandin E2 (PGE2), promotes tissue repair and regeneration in many organs. PGE2 causes intrarenal arterial vasodilation. In this study, we investigated whether a 15-PGDH inhibitor can act as a candidate for blocking these two major mechanisms of CIAKI. We established a CIAKI mouse model by injecting a 10 gram of iodine per body weight (gI/kg) dose of iodixanol into each mouse tail vein. A 15-PGDH inhibitor (SW033291), PGE1, or PGE2 were administered to compare the renal functional parameters, histologic injury, vasoconstriction, and renal blood flow changes. In addition, human renal proximal tubular epithelial cells were cultured in a CM-treated medium. SW033291, PGE1, or PGE2 were added to compare any changes in cell viability and apoptosis rate. CIAKI mice that received SW033291 had lower serum levels of creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 (p < 0.001); lower histologic injury score and TUNEL positive rates (p < 0.001); and higher medullary arteriolar area (p < 0.05) and renal blood flow (p < 0.001) than CM + vehicle group. In cell culture experiments, Adding SW033291 increased the viability rate (p < 0.05) and decreased the apoptosis rate of the tubular epithelial cells (p < 0.001). This 15-PGDH inhibitor blocks the two primary mechanisms of CIAKI, intrarenal vasoconstriction and tubular cell toxicity, and thus has the potential to be a novel prophylaxis for CIAKI. Abbreviations: 15-PGDH: 15-hydroxyprostaglandin dehydrogenase; AMP: adenosine monophosphate; CIAKI: contrast-induced acute kidney injury; CM: contrast media; EP: prostaglandin E2 receptor; hRPTECs: human-derived renal proximal tubule epithelial cells; KIM-1: kidney injury molecule-1; MTT: 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NGAL: neutrophil gelatinase-associated lipocalin; PBS: phosphate-buffered saline; PGE1: prostaglandin E1; PGE2: prostaglandin E2; RBF: renal blood flow; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; α-SMA: α-Smooth muscle actin

Renal medullary oxygenation decreases with lower body negative pressure in healthy young adults.

One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negative pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; -10, -20, and -30 mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; n = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured (n = 13) as LBNP was instituted. LBNP significantly reduced RBV (P = 0.041) at -30 mmHg of LBNP (Δ-8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP P = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla.NEW & NOTEWORTHY In healthy young adults, increased sympathetic activation induced by lower body negative pressure, led to a decrease in renal cortical and medullary oxygenation measured by T2*, a noninvasive magnetic resonance derived index of deoxyhemoglobin levels. In this study, we observed a significant decrease in renal cortical and medullary oxygenation with LBNP as well as an increase in renal vasoconstriction. We speculate that sympathetic renal vasoconstriction led to a significant reduction in tissue oxygenation by limiting oxygen delivery to the renal medulla.

Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats.

Pioglitazone, a therapeutic drug for diabetes, possesses full PPAR-γ agonist activity and increase circulating adiponectin plasma concentration. Plasma adiponectin concentration decreases in hypertensive patients with renal dysfunctions. Present study investigated the reno-protective, altered excretory functions and renal haemodynamic responses to adrenergic agonists and ANG II following separate and combined therapy with pioglitazone in diabetic model of hypertensive rats. Pioglitazone was given orally [10mg/kg/day] for 28 days and adiponectin intraperitoneally [2.5μg/kg/day] for last 7 days. Groups of SHR received either pioglitazone or adiponectin in combination. A group of Wistar Kyoto rats [WKY] served as normotensive controls, whereas streptozotocin administered SHRs served as diabetic hypertensive rats. Metabolic data and plasma samples were taken on day 0, 8, 21 and 28. In acute studies, the renal vasoconstrictor actions of Angiotensin II [ANGII], noradrenaline [NA], phenylephrine [PE] and methoxamine [ME] were determined. Diabetic SHRs control had a higher basal mean arterial blood pressure than the WKY, lower RCBP and plasma adiponectin, higher creatinine clearance and urinary sodium excretion compared to WKY [all P<0.05] which were normalized by the individual drug treatments and to greater degree following combined treatment. Responses to intra-renal administration of NA, PE, ME and ANGII were larger in diabetic SHR than WKY and SHRs [P<0.05]. Adiponectin significantly blunted responses to NA, PE, ME and ANG II in diabetic treated SHRs by 40%, whereas the pioglitazone combined therapy with adiponectin further attenuated the responses to adrenergic agonists by 65%. [all P <0.05]. These findings suggest that adiponectin possesses renoprotective effects and improves renal haemodynamics through adiponectin receptors and PPAR-γ in diabetic SHRs, suggesting that synergism exists between adiponectin and pioglitazone. A cross-talk relationship also supposed to exists between adiponectin receptors, PPAR-γ and alpha adrenoceptors in renal vasculature of diabetic SHRs.

Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

The kidney is extensively innervated by sympathetic nerves playing an important role in the regulation of blood pressure homeostasis. Sympathetic nerve activity is ultimately controlled by the central nervous system (CNS). Norepinephrine, the main sympathetic neurotransmitter, is released at prejunctional neuroeffector junctions in the kidney and modulates renin release, renal vascular resistance, sodium and water handling, and immune cell response. Under physiological conditions, renal sympathetic nerve activity (RSNA) is modulated by peripheral mechanisms such as the renorenal reflex, a complex interaction between efferent sympathetic nerves, central mechanism, and afferent sensory nerves. RSNA is increased in hypertension and, therefore, critical for the perpetuation of hypertension and the development of hypertensive kidney disease. Renal sympathetic neurotransmission is not only regulated by RSNA but also by prejunctional α2-adrenoceptors. Prejunctional α2-adrenoceptors serve as autoreceptors which, when activated by norepinephrine, inhibit the subsequent release of norepinephrine induced by a sympathetic nerve impulse. Deletion of α2-adrenoceptors aggravates hypertension ultimately by modulating renal pressor response and sodium handling. α2-adrenoceptors are also expressed in the vasculature, renal tubules, and immune cells and exert thereby effects related to vascular tone, sodium excretion, and inflammation. In the present review, we highlight the role of α2-adrenoceptors on renal sympathetic neurotransmission and its impact on hypertension. Moreover, we focus on physiological and pathophysiological functions mediated by non-adrenergic α2-adrenoceptors. In detail, we discuss the effects of sympathetic norepinephrine release and α2-adrenoceptor activation on renal sodium transporters, on renal vascular tone, and on immune cells in the context of hypertension and kidney disease.

Pre-treatment with the angiotensin receptor 1 blocker losartan protects renal blood flow and oxygen delivery after propofol-induced hypotension in pigs

Hypotensive events are strongly correlated to the occurrence of perioperative acute kidney injury, but the underlying mechanisms for this are not completely elucidated. We hypothesised that anaesthesia-induced hypotension causes renal vasoconstriction and decreased oxygen delivery via angiotensin II-mediated renal vasoconstriction. Pigs were anaesthetised, surgically prepared and randomised to vehicle/losartan treatment (0.15 mg*kg−1). A deliberate reduction in arterial blood pressure was caused by infusion of propofol (30 mg*kg−1) for 10 min. Renal function and haemodynamics were recorded 60 min before and after hypotension. Propofol induced hypotension in all animals (p < 0.001). Renal blood flow (RBF) and renal oxygen delivery (RDO2) decreased significantly regardless of treatment but more so in vehicle-treated compared to losartan-treated (p = 0.001, p = 0.02, respectively). During recovery RBF and RDO2 improved to a greater extent in the losartan-treated compared to vehicle-treated (+ 28 ml*min−1, 95%CI 8–50 ml*min−1, p = 0.01 and + 3.1 ml*min−1, 95%CI 0.3–5.8 ml*min−1, p = 0.03, respectively). Sixty minutes after hypotension RBF and RDO2 remained depressed in vehicle-treated, as renal vascular resistance was still increased (p < 0.001). In losartan-treated animals RBF and RDO2 had normalised. Pre-treatment with losartan improved recovery of renal blood flow and renal oxygen delivery after propofol-induced hypotension, suggesting pronounced angiotensin II-mediated renal vasoconstriction during blood pressure reductions caused by anaesthesia.

The Effect of Door to Wire Crossing and the Incidence of Acute Kidney Injury in ST Segment Elevation Myocardial Infarction Patients Underwent Primary Percutaneous Coronary Intervention at H. Adam Malik Hospital Medan

Background: ST segment elevation myocardial infarction (STEMI) causes hemodynamic changes and an increase in endogenous vasoconstrictor release leads to renal arteriolar vasoconstriction and decreases renal perfusion and may causes acute kidney injury (AKI). Door to wire crossing is a very important prognostic marker in STEMI patients.&#x0D; Aims: To assess the effect of door to wire crossing and the incidence of AKI in STEMI patients with onset &lt;12 hours undergoing primary percutaneous coronary intervention (PCI) at H. Adam Malik General Hospital Medan.&#x0D; Methods: This study is a cohort study conducted from October 2018 to July 2019 with study subjects of STEMI patients with onset &lt;12 hours who underwent primary PCI that met the inclusion and exclusion criteria. Creatinine levels will be checked before and 48-72 hours after the primary PCI as well as the door to wire crossing will be recorded and compared.&#x0D; Result: The incidence of AKI was found around 14% in the group with a door to wire crossing &lt;140 minutes and by 39% in the group with a door to wire crossing&gt; 140 minutes. It was found that the final urea (p = 0.03), creatinine (p = 0.01), CrCl (p = 0.004) and changes in creatinine (p = 0.008) were statistically significant, while the contrast volume was not. In addition, the door to wire cossing &gt;140 minutes (OR: 4.6; p = 0.032), hypertension (OR: 5.96; p = 0.018) and STEMI onset &gt;6 hours (OR: 7.3; p = 0.019) emerged as independent predictors of AKI.&#x0D; Conclusion: STEMI patients with onset &lt;12 hours who underwent primary PCI with the door to wire cossing &gt;140 minutes have 4.6 times likelihood to develop AKI rather than those with door to wire cossing &lt;140 minutes. The incidence of AKI ranges from 14% -39%. The independent predictors of AKI besides door to wire crossing are hypertension and STEMI's onset.

Latest Clinical Evidence About Effect of Acetylcysteine on Preventing Contrast-Induced Nephropathy in Patients Undergoing Angiography: A Meta-Analysis.

Contrast-induced nephropathy (CIN) is a serious complication of angiographic procedures. It is the third most common cause of hospital acquired acute renal injury. As there are currently no approved therapies for CIN, prevention could be the best strategy to address this issue. Acetylcysteine may indirectly play an antioxidant role by inducing the synthesis of glutathione. Acetylcysteine can also reduce renal vasoconstriction induced by contrast medium stimulation by stabilizing nitric oxide and acting directly or indirectly on renal cortex and medulla microcirculation. To evaluate the effect of acetylcysteine on the prevention of CIN in patients after angiography, we systematically searched and analyzed the clinical data of patients including the incidence of CIN and change in serum creatinine (SCr) at 48 hours after angiography from selected articles. The result showed that acetylcysteine significantly reduces the incidence of CIN (risk ratios: 0.78, 95% CI: 0.68-0.90, I2 = 37.3%) and the level of SCr (standardized mean difference: -0.53, 95% CI: -0.93 to -0.12, I2 = 91.5%) after angiography compared with the control group. Overall, the use of acetylcysteine in patients after angiography was associated with a significant reduction of CIN and the level of SCr.

Dietary Potassium Downregulates Angiotensin-I Converting Enzyme, Renin, and Angiotensin Converting Enzyme 2.

BackgroundThe importance of dietary potassium in health and disease has been underestimated compared with that placed on dietary sodium. Larger effort has been made on reduction of sodium intake and less on the adequate dietary potassium intake, although natural food contains much more potassium than sodium. The benefits of a potassium-rich diet are known, however, the mechanism by which it exerts its preventive action, remains to be elucidated. With the hypothesis that dietary potassium reduces renal vasoconstrictor components of the renin-angiotensin system in the long-term, we studied the effect of high potassium diet on angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2.MethodsSprague Dawley male rats on a normal sodium diet received normal potassium (0.9%, NK) or high potassium diet (3%, HK) for 4 weeks. Urine was collected in metabolic cages for electrolytes and urinary volume measurement. Renal tissue was used to analyze angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2 expression. Protein abundance analysis was done by Western blot; gene expression by mRNA levels by RT-qPCR. Renal distribution of angiotensin-I converting enzyme and renin was done by immunohistochemistry and morphometric analysis in coded samples.ResultsHigh potassium diet (4 weeks) reduced the levels of renin, angiotensin-I converting enzyme, and angiotensin converting enzyme 2. Angiotensin-I converting enzyme was located in the brush border of proximal tubules and with HK diet decreased the immunostaining intensity (P < 0.05), decreased the mRNA (P < 0.01) and the protein levels (P < 0.01). Renin localization was restricted to granular cells of the afferent arteriole and HK diet decreased the number of renin positive cells (P < 0.01) and renin mRNA levels (P < 0.01). High potassium intake decreased angiotensin converting enzyme 2 gene expression and protein levels (P < 0.01).No morphological abnormalities were observed in renal tissue during high potassium diet.The reduced expression of angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2 during potassium supplementation suggest that high dietary potassium intake could modulate these vasoactive enzymes and this effects can contribute to the preventive and antihypertensive effect of potassium.

The Role of P2X7 Purinergic Receptors in the Renal Inflammation Associated with Angiotensin II-induced Hypertension.

Purinergic receptors play a central role in the renal pathophysiology of angiotensin II-induced hypertension, since elevated ATP chronically activates P2X7 receptors in this model. The changes induced by the P2X antagonist Brilliant blue G (BBG) in glomerular hemodynamics and in tubulointerstitial inflammation resulting from angiotensin II infusion were studied. Rats received angiotensin II (435 ng kg−1 min−1, 2 weeks) alone or in combination with BBG (50 mg/kg/day intraperitoneally). BBG did not modify hypertension (214.5 ± 1.4 vs. 212.7 ± 0.5 mmHg), but restored to near normal values afferent (7.03 ± 1.00 to 2.97 ± 0.27 dyn.s.cm−5) and efferent (2.62 ± 0.03 to 1.29 ± 0.09 dyn.s.cm−5) arteriolar resistances, glomerular plasma flow (79.23 ± 3.15 to 134.30 ± 1.11 nL/min), ultrafiltration coefficient (0.020 ± 0.002 to 0.036 ± 0.003 nL/min/mmHg) and single nephron glomerular filtration rate (22.28 ± 2.04 to 34.46 ± 1.54 nL/min). Angiotensin II induced overexpression of P2X7 receptors in renal tubular cells and in infiltrating T and B lymphocytes and macrophages. All inflammatory cells were increased by angiotensin II infusion and reduced by 20% to 50% (p < 0.05) by BBG administration. Increased IL-2, IL-6, TNFα, IL-1β, IL-18 and overexpression of NLRP3 inflammasome were induced by angiotensin II and suppressed by BBG. These studies suggest that P2X7 receptor-mediated renal vasoconstriction, tubulointerstitial inflammation and activation of NLRP3 inflammasome are associated with angiotensin II-induced hypertension.