Increase In Renal Plasma Flow Research Articles

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals.

Disease-causing mutations in CACNA1D gene occur in aldosterone-producing adenomas and familial hyperaldosteronism. We determined whether single nucleotide polymorphisms in CACNA1D gene associate with higher aldosterone resulting in salt sensitivity of blood pressure (BP) and increased BP in men and women. Data were obtained from the HyperPATH (International Hypertension Pathotypes) cohort, where participants completed a cross-over intervention of liberal and restricted sodium diets. Multi-Ethnic Genotyping Array identified 104 CACNA1D single nucleotide polymorphisms that met quality control. Single nucleotide polymorphism is rs7612148 strongly associated with systolic BP and was selected for study in 521 White participants in 3 scenarios ([1] hypertensives; [2] normotensives; [3] total population=hypertensives+normotensives) using multivariate regression analysis. In the total population and hypertensives, but not normotensives, risk allele carriers (CC, GC), as compared with nonrisk allele homozygotes (GG), exhibited higher salt sensitivity of BP and, on liberal sodium diet, higher systolic BP, lower baseline and angiotensin II-stimulated aldosterone, and lower plasma renin activity. On restricted sodium diet, BP was similar across genotypes, suggesting sodium restriction corrected/neutralized the genotype effect on BP. Because increased aldosterone did not seem to drive the increased salt sensitivity of BP and increased BP on liberal sodium diet, we assessed renal plasma flow. Renal plasma flow increase from restricted to liberal sodium diets was blunted in risk allele homozygotes in the total population and in hypertensives. A replication study in another cohort HyperPATH B (International Hypertension Pathotypes Cohort B) confirmed BP-genotype associations. CACNA1D rs7612148 risk allele associated with increased BP and salt sensitivity of BP, likely due to an impaired ability to increase renal plasma flow in response to a liberal sodium diet and not to excess aldosterone.

P0002A NEW INSIGHT INTO THE MECHANISM OF HYPERCHLOREMIC METABOLIC ACIDOSIS IN KIDNEY TRANSPLANT RECIPIENTS: INCREASED POSTGLOMERULAR PERITUBULAR BLOOD FLOW IS A KEY CONDITION FOR THE DEVELOPEMENT OF CALCINEURIN INHIBITOR-INDUCED RENAL TUBULAR ACIDOSIS

Abstract Background and Aims Hyperchloremic metabolic acidosis (HCMA) due to renal tubular acidosis is a common complication in kidney transplant recipients(KTR). Potential renal dysfunction, rejection, ischemia, persistent hyperparathyroidism, calcineurin inhibitors (CNIs), etc. have been identified as causes but have not been fully proven, and whether HCMA is a determinant of poor graft prognosis in KTR is still controversial. The purpose of this study is to elucidate the actual mechanism of HCMA in KTR. Method HCMA was defined as follows: i) simple strong ion difference (SID) Na-CL, which is the most dominant metabolic factor in physicochemical approach for acid-base balance, is 34 or less, or â…±) the alkalizing drugs have been started after the KT to correct HCMA. And all the cases of having diarrhea from mycophenolate mofetil(MMF), and gastroenterocolitis from cytomegalovirus infection were excluded. The study group consisted of 47 KTRs who underwent living-kidney transplantation(KT) at our hospital as well as a control group of 43 of the matched donors. Among them, a total of 26 KTRs received the renal hemodynamic studies which were based on urinary clearance of inulin and para-aminohippuric acid 1year after KT. 1) The incidence of HCMA in KTR at 3 months(3m) and 1 year(1y) after KT were examined. 2) To elucidate factors related to HCMA in KTR at 1y, we comprehensively examined factors and compared HCMA groups with non-HCMA groups; donor and recipient background (gender, age, body size), immunological factors, information on transplant surgery, salt and protein intake, effective buffering factors for extracellular body fluids such as albumin and hemoglobin, serum calcium and phosphate concentrations and their ratios, administration of renin-angiotensin system inhibitors and diuretics,Tac trough level and Banff score of each histopathological lesion in 1y biopsy. As for the 26 KTRs who received the renal hemodynamic studies, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction(FF) (GFR/RPF) and pre-/post-glomerular vascular resistance (pre-/postVR) calculated from the Gomez' equations were also analyzed. Results 1) The incidence of HCMA in the KTR at 3m was 51% (24/47), which was much higher than the 6.9% (3/43) in those donors (p<0.001), and the range of odds ratios (vs donor) adjusted by the background factors (age,gender, estimated GFR, albumin and hemoglobin) was 6.7-15.7 (p=0.0001-0.001). The incidence of HCMA in KTR at 1y decreased to 34%. 2)The univariate analysis of HCMA in KTR at 1y compared with non-HCMA showed an increase in RPF (p= 0.016), a decrease in post-VR (p= 0.003), and a decrease in FF (p= 0.0001), suggesting an increase in post-glomerular peritubular blood flow. In addition, the aah lesion score, an indicator of CNI vasculopathy, was also significantly higher in the HCMA (p = 0.015). There was no difference in Tac trough levels between HCMA and nonHCMA, and no independent factors were found by multivariate analysis. All cases with HCMA were classified into low post-VR (Fig.1). Furthermore, in low post-VR alone (n= 15), the Tac trough level at 1y was significantly higher in the HCMA (p= 0.002) (Fig.2). Conclusion In kidney transplant recipients, increased post-glomerular peritubular blood flow is a key condition for the development of CNI-induced renal tubular acidosis. The presence of HCMA suggests that it is probably not a serious condition, but rather a desirable hemodynamic state, however, more attention should be paid not to elevate CNI concentration levels in such conditions.

Differential Impact of Dietary Branched Chain and Aromatic Amino Acids on Chronic Kidney Disease Progression in Rats.

The metabolism of dietary proteins generates waste products that are excreted by the kidney, in particular nitrogen-containing urea, uric acid, ammonia, creatinine, and other metabolites such as phosphates, sulfates, and protons. Kidney adaptation includes an increase in renal plasma flow (RPF) and glomerular filtration rate (GFR) and represents a burden for diseased kidneys increasing the progression rate of CKD. The present study aimed at identifying potential differences between amino acid (AA) groups constituting dietary proteins regarding their impact on RPF, GFR, and CKD progression. We utilized the well-established 5/6 nephrectomy (5/6 Nx) CKD model in rats and submitted the animals for 5 weeks to either the control diet (18% casein protein) or to diets containing 8% casein supplemented with 10% of a mix of free amino acids, representing all or only a subset of the amino acids contained in casein. Whereas the RPF and GFR measured in free moving animals remained stable during the course of the diet in rats receiving the control mix, these parameters decreased in animals receiving the branched chain amino acid (BCAA) supplementation and increased in the ones receiving the aromatic amino acids (AAAs). In animals receiving essential amino acids (EAAs) containing both BCAAs and AAAs, there was only a small increase in RPF. The kidneys of the 5/6 Nx rats receiving the BCAA diet showed the strongest increase in smooth muscle actin and collagen mRNA expression as a result of higher level of inflammation and fibrosis. These animals receiving BCAAs also showed an increase in plasma free fatty acids pointing to a problem at the level of energy metabolism. In contrast, the animals under AAA diet showed an activation of AMPK and STAT3. Taken together, our results demonstrate that subsets of EAAs contained in dietary proteins, specifically BCAAs and AAAs, exert contrasting effects on kidney functional parameters and CKD progression.

Relaxin-mediated renal vasodilation in the rat is associated with falls in glomerular blood pressure.

Relaxin (RLX) is a pleiotropic peptide hormone with marked renal vasodilatory actions that are physiologically important during pregnancy. RLX also has potent antifibrotic actions and is being tested therapeutically in various fibrotic diseases, including chronic kidney disease (CKD). Since renal vasodilation may expose the glomerulus to increased blood pressure [glomerular capillary pressure (PGC)], which exacerbates progression of CKD, we assessed the glomerular hemodynamic actions of acute (0.89 µg·100 g body wt-1·h-1 iv over 75 min) and chronic (1.5 µg·100 g body wt-1·h-1 sc) administration of RLX. Both acute and chronic RLX produced marked renal vasodilation and increased renal plasma flow (RPF) in euvolemic, anesthetized male rats. Glomerular filtration rate also increased with RLX, but the magnitude of the rise was much less than the increase in RPF due to concomitant decreases in filtration fraction. The fall in filtration fraction was the result of significant decreases in PGC, despite a slight increase in mean arterial blood pressure (MAP) with acute RLX and no net change in MAP with chronic RLX. This fall in PGC occurred because of the "in-series" arrangement of the afferent and efferent arteriolar resistance vessels, which can regulate PGC independently of MAP. With both acute and chronic RLX, efferent arteriolar resistance vessels relaxed to a greater extent than afferent arteriolar resistance vessels, thus producing falls in PGC. Based on this finding, RLX has a beneficial hemodynamic impact on the kidney, which, together with the antifibrotic actions of RLX, suggests a strong therapeutic potential for use in CKD.

PP.15.32] NEW MODEL TO INVESTIGATE THE INFLUENCE OF AIRCRAFT NOISE IN THE PATHOPHYSIOLOGICAL CONCEPT OF HYPERTENSION

Objective: Epidemiological studies have found a link between aircraft noise exposure and increased incidence of arterial hypertension and thus cardiovascular disease. The underlying pathophysiological mechanisms are not yet fully understood. The kidney acts as a long-term regulator of blood pressure and controls the extracellular sodium and water balance. Animal work and clinical studies show that mental stress affects the renal plasma flow and central hemodynamics. Design and method: We could establish a model to analyse the influence of 30 minutes standardized aircraft noise with a maximal sound pressure level of 80 dB on renal and central hemodynamics in 80 healthy volunteers. Renal hemodynamics were investigated using the clearance analysis with infusion of paraaminohippuric acid (PAH) and Inulin. Central hemodynamics were analysed using cardio impedance tomography. Results: Cardio impedance tomography showed no difference in RR-ECG duration (978 ± 143 vs. 907 ± 199 ms, p = 0.072), heart frequency (63 ± 9 vs 66 ± 10 bpm, p = 0.130), cardiac index (3.3 ± 0.65 vs 3.5 ± 0.82 l/min/m2, p = 0.330) and total peripheral resistance index (2031 ± 622 vs 2032 ± 655, p = 0.998) in persons after noise exposure compared to sham exposed individuals. There were no significant differences in renal plasma flow (698 ± 124 vs. 693 ± 123 ml/min, p = 0.215) and glomerular filtration rate (152 ± 19 vs 151 ± 18 ml/min, p = 0.626) between noise and sham exposed individuals. There was an increase in renal plasma flow between baseline (688 ± 120 ml/min) and noise exposure (698 ± 124 ml/min, p = 0.011). Conclusions: We established a model to investigate the influence of aircraft noise on renal and central hemodynamics. In healthy individuals there was no change in central hemodynamics caused by short term aircraft noise exposure. Renal plasma flow increased between baseline and noise exposure, possibly pointing to a change in renal hemodynamics. We plan to extend our population to 44 hypertensive patients.

Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence.

Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men. The actions of serelaxin are primarily via nitric oxide, leading to the observed vasodilatory effects, and increase in renal plasma flow. It has also been found to increase expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9. The antifibrotic and antiinflammatory effects of the drug also play a role in heart failure. In Phase II studies, serelaxin has shown reduction in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP. The recently published results of the RELAX-AHF, a phase III clinical trial on serelaxin, has opened new avenues into our understanding of its effects in heart failure. The trial showed improvement in short-term dyspnea scores and 180-day mortality, but, interestingly, failed to show any improvement of the secondary endpoints of death or readmission at 60days. Ongoing Phase III trials like RELAX-AHF-2 and RELAX-AHF-ASIA would explain these data better and improve understanding of the use of serelaxin in clinical practice. This article summarizes the most updated published preclinical and clinical study data on serelaxin, including pharmacokinetic, pharmacodynamic, safety studies in hepatic, renal impaired patients, Phase II and Phase III trials.

The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone system.

Pregnancy is characterized by avid renal sodium retention and plasma volume expansion in the presence of decreased blood pressure. Decreased maternal blood pressure is a consequence of reduced systemic vascular tone, which results from an increased production of vasodilators [nitric oxide (NO), prostaglandins, and relaxin] and decreased vascular responsiveness to the potent vasoconstrictor (angiotensin II). The kidneys participate in this vasodilatory response, resulting in marked increases in renal plasma flow and glomerular filtration rate (GFR) during pregnancy. In women, sodium retention drives plasma volume expansion (∼40%) and is necessary for perfusion of the growing uterus and fetus. For there to be avid sodium retention in the presence of the potent natriuretic influences of increased NO and elevated GFR, there must be modifications of the tubules to prevent salt wasting. The purpose of this review is to summarize these adaptations.

Maximum renal responses to renin inhibition in healthy study participants

Renin inhibition with aliskiren induced the largest increases in renal plasma flow (RPF) in salt-depleted healthy volunteers of all renin-angiotensin system (RAS) blockers. However, given its side-effects at doses higher than 300 mg, no maximum effect of renin inhibition could be established. We hypothesized that VTP-27999, a novel renin inhibitor without major side-effects at high doses, would allow us to establish this. The effects of escalating VTP-27999 doses (75-600 mg) on RPF, glomerular filtration rate (GFR), and plasma RAS components were compared with those of 300 mg aliskiren in 22 normal volunteers on a low-sodium diet. VTP-27999 dose-dependently increased RPF and GFR; its effects on both parameters at 600 mg (increases of 18 ± 4 and 20 ± 4%, respectively) were equivalent to those at 300 mg, indicating that a maximum had been reached. The effects of 300 mg aliskiren (increases of 13 ± 5 and 8 ± 6%, respectively; P < 0.01 vs. 300 and 600 mg VTP-27999) resembled those of 150 mg VTP-27999. VTP-27999 dose-dependently increased renin, and lowered plasma renin activity and angiotensin II to detection limit levels. The effects of aliskiren on RAS components were best comparable to those of 150 mg VTP-27999. Maximum renal renin blockade in healthy, salt-depleted volunteers, requires aliskiren doses higher than 300 mg, but can be established with 300 mg VTP-27999. To what degree such maximal effects (exceeding those of angiotensin-converting enzyme inhibitors and AT1-receptor blockers) are required in patients with renal disease, given the potential detrimental effects of excessive RAS blockade, remains to be determined.

تقييم وظائف الكلى لدى الحوامل السعوديات بمنطقة جازان

تظهر تغيرات ديناميكية الدم الكلوية الملحوظة بنهاية الثلث الأول من الحمل. كلا الكبيبي معدل الترشيح وتدفق البلازما الكلوي الفعال يزيد بنسبة 50٪ من النساء الحوامل. من المحتمل أن يكون تدفق البلازما الكلوي الفعال يزداد إلى حد كبير ، وبالتالي ، ينخفض ​​جزء الترشيح أثناء الحمل المبكر والمتوسط. الأهداف: للتقييم مستويات مصل وظائف الكلى بين النساء الحوامل السعوديات في منطقة جازان. المواد والطرق: دراسة مستقبلية تعتمد على الحالات والشواهد في المستشفى أجريت في منطقة جازان من مارس 2014 إلى يونيو 2015. 30 امرأة حامل تم اختياره في مستشفى جازان العام وتقييمه لاختبارات وظائف الكلى. تم اختيار 30 من الأشخاص الأصحاء كمجموعة تحكم كانوا العمر ، والاجتماعية والاقتصادية المتطابقة مع مجموعة الحمل. تم استخدام SPSS لتحليل البيانات باستخدام اختبار الطالب ‟t و Pearson الارتباط لتقييم الارتباط بين المتغيرات المختلفة. النتائج: كان هناك فرق معنوي في متوسط ​​مستويات اليوريا والكرياتينين في الدم في مجموعة الاختبار (p &lt;0.05) بالمقارنة مع مجموعة السيطرة مع وجود ارتباط إيجابي معتدل معنوي بين مستويات الكرياتينين في الدم مع فترة الحمل. الخلاصة: انخفاض مستويات اليوريا والكرياتينين في الدم بشكل ملحوظ عند النساء الحوامل في المملكة العربية السعودية. يشير الانخفاض التدريجي في مستويات اليوريا والكرياتينين خلال الأشهر الثلاثة الأخيرة من الحمل إلى زيادة في معدل الترشيح الكبيبي ، وربما يرجع ذلك إلى زيادة معدل ضربات القلب. الإخراج وتدفق الدم الكلوي والتغيرات في توزيع السوائل.

Cardiovascular physiology of pregnancy.

Pregnancy is a dynamic process associated with significant physiological changes in the cardiovascular system. These changes are mechanisms that the body has adapted to meet the increased metabolic demands of the mother and fetus and to ensure adequate uteroplacental circulation for fetal growth and development. Insufficient hemodynamic changes can result in maternal and fetal morbidity, as seen in preeclampsia and intrauterine growth retardation. In addition, maternal inability to adapt to these physiological changes can expose underlying, previously silent, cardiac pathology, which is why some call pregnancy nature’s stress test. Indeed, cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America.1 We therefore review here the normal cardiovascular physiology of pregnancy to provide clinicians with a basis for understanding how the presence of cardiovascular disease may compromise the mother and fetus and how their decisions about medical care may need adjustment. Pregnancy is associated with vasodilation of the systemic vasculature and the maternal kidneys. The systemic vasodilation of pregnancy occurs as early as at 5 weeks and therefore precedes full placentation and the complete development of the uteroplacental circulation.2 In the first trimester, there is a substantial decrease in peripheral vascular resistance, which decreases to a nadir during the middle of the second trimester with a subsequent plateau or slight increase for the remainder of the pregnancy3 (Figure 1). The decrease is ≈35% to 40% of baseline. Systemic vascular resistance increases to near-prepregnancy levels postpartum,4 and by 2 weeks after delivery, maternal hemodynamics have largely returned to nonpregnant levels.5 Increased vascular distensibility, or compliance, has been observed in normal human pregnancy starting in the first trimester.6 Systemic vascular resistance increases to near-prepregnancy levels postpartum.4 Vasodilation of the kidneys results in a 50% increase in renal plasma flow and glomerular filtration …

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

During the first trimester of human pregnancy, the maternal systemic circulation undergoes remarkable vasodilation. The kidneys participate in this vasodilatory response resulting in marked increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). Comparable circulatory adaptations are observed in conscious gravid rats. Administration of the corpus luteal hormone relaxin (RLN) to nonpregnant rats and humans elicits vasodilatory changes like those of pregnancy. Systemic and renal vasodilation are compromised in midterm pregnant rats by neutralization or elimination of circulating RLN and in women conceiving with donor eggs who lack a corpus luteum and circulating RLN. Although RLN exerts both rapid (minutes) and sustained (hours to days) vasodilatory actions through different molecular mechanisms, a final common pathway is endothelial nitric oxide. In preeclampsia (PE), maternal systemic and renal vasoconstriction leads to hypertension and modest reduction in GFR exceeding that of RPF. Elevated level of circulating soluble vascular endothelial growth factor receptor-1 arising from the placenta is implicated in the hypertension and disruption of glomerular fenestrae and barrier function, the former causing reduced Kf and the latter proteinuria. Additional pathogenic factors are discussed. Last, potential clinical ramifications include RLN replacement in women conceiving with donor eggs and its therapeutic use in PE. Another goal has been to apply knowledge gained from investigating circulatory adaptations in pregnancy toward identifying and developing novel therapeutic strategies for renal and cardiovascular disease in the nonpregnant population. So far, one candidate to emerge is RLN and its potential therapeutic use in heart failure.

Synthetic oleanane triterpenoids: magic bullets or not?

A recent clinical trial in patients with chronic kidney disease (CKD) and diabetic nephropathy demonstrated that bardoxolone methyl (CDDO-ME) increases estimated glomerular filtration rate (eGFR) by an unknown mechanism. The paper by Ding et al. suggests that short-term administration of a CDDO-ME analog increases GFR by increasing glomerular surface area. However, changes in other renal hemodynamic parameters cannot be excluded. Vigorous testing of CDDO-ME and highly purified analogs is warranted to determine their physiology, pharmacology, and efficacy and to exclude serious side effects.

A comparative study of renal function in male and female spiny mice – sex specific responses to a high salt challenge

BackgroundThere is a significant body of evidence to suggest that hormone levels, receptor density and structural differences between males and females can significantly alter renal hemodynamics. We compared the renal hemodynamic and excretory profile of female and male spiny mice under baseline conditions and in response to a high-NaCl diet.MethodsAdult male and female spiny mice were fed either a normal or high salt diet for 7 days. Renal excretory profile was obtained from 24 h urine samples, and renal hemodynamic measurements using anaesthetised renal clearance techniques. Kidneys were excised, weighed and frozen for qPCR analysis.ResultsUnder basal conditions, conscious and anaesthetised renal functions were similar between male and female spiny mice when adjusted for body weights. Male and female spiny mice on the high-NaCl diet had significantly greater GFR than sex matched controls (PDIET < 0.001). However the magnitude of the effect of salt was sex dependent (PSEX < 0.001; PINT < 0.01). Male spiny mice showed a greater increase in GFR (84% higher than normal salt males) compared to females (33% higher than normal salt females), despite similar increases in renal plasma flow. In response to 7 days of high salt diet, female spiny mice showed a greater increase in 24-hour water consumption (45% more) and urinary output (50% more) compared to males (PINT < 0.01). These sex differences could not be explained by differences in renal expression of the V2R or AQP3 channel.ConclusionThese studies have identified major differences between male and female spiny mice in their renal response to a high-NaCl load suggesting that renal hemodynamics may be differentially regulated for the sexes.

Renal Sympathetic Denervation for Treating Resistant Hypertension

Systemic hypertension represents a significant global concern, because it contributes to vascular and renal morbidity, cardiovascular mortality, and economic burden, hence the impact of hypertension is a major issue in public health worldwide. Improving high blood pressure management is therefore fundamental to influencing clinical outcomes. Despite adherence to multiple available medical therapies, a significant proportion of patients has persistent blood pressure elevation, a condition termed "resistant hypertension". Renal sympathetic innervations contribute to lack of response of anti-hypertensive drugs through an imbalance of regulatory mechanisms. Renal afferent nerve fibers are responsible for sympathetic activation and contribute to blood pressure homeostasis while afferent signals from the kidneys are integrated at the central nervous system and enhance sympathetic nerve discharge. In this regard, a novel strategy that selectively removes these hypertensive contributors represents a new therapeutic opportunity. Recently, a catheter-based method to induce renal sympathetic denervation has been introduced into daily practice. Clinical evaluation of selective renal sympathetic denervation demonstrated a decrease of renal norepinephrine spillover and renin activity, an increase of renal plasma flow, and has confirmed clinically significant, sustained reductions in blood pressure in patients with resistant hypertension. This review summarizes the available data on the role of sympathetic activation in the pathophysiology of hypertension and the current concepts in transcatheter renal artery ablation with radiofrequency delivery for systemic hypertension. Suggestions regarding targets for future systemic hypertension management are also described.

Systemic and renal haemodynamic changes in renal schemia/reperfusion injury: impact of erythropoietin

The objective of this study was to investigate the effects of erythropoietin (EPO) on systemic and renal hemodynamics in a rat model of renal ischemic/reperfusion (I/R) injury. We used 30 male Sprague-Dawley rats distributed among the following 3 groups (10 rats per group): (i) the sham-operated group, (ii) the control group (I/R injury only), and (iii) the EPO-treated group (I/R injury with 1500 U EPO·(kg body mass)⁻¹ on day 0, and 500 U·kg⁻¹ on days 2 and 4 after ischemia). Renal function, arterial blood pressure (ABP), renal plasma flow (RPF), renal blood flow (RBF), and renal vascular resistance (RVR) were measured on days 1, 2, and 7 after ischemia. The expression of endothelial NO synthase (eNOS) and histopathology of kidney were evaluated on day 7. The contractility of aortic strips was recorded from the different groups. The results show that renal function and histopathology were significantly improved after treatment with EPO. Compared with the control group, the EPO-treated group showed a significant increase in RPF, RBF, haematocrite, ABP, eNOS expression, and a decrease in RVR (p < 0.05).The response of aortic strips to the relaxant effect of acetylcholine was improved in the EPO-treated group. In conclusion, treatment with EPO improves renal function and renal haemodynamics in renal I/R injury, and causes significant rise of ABP and haematocrite value.

Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 μg·kg(-1)·min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.

Renal clearance procedure for the rat: effect of dopamine and standard saluretics.

Four standard diuretic compounds were evaluated for electrolyte output, effects on glomerular filtration rate (GFR), and effective renal plasma flow (RPF) in an anaesthetized rat preparation. Triamterene, hydrochlorothiazide, acetazoleamide and furosemide exerted their characteristic diuretic effects at doses which did not significantly change GFR or RPF. Regulation of the rate of a 3% mannitol-0.9% NaCl infusion to rats permitted the establishment of GFR and RPF values which were approximately in the middle of the reported range for this species. A significant increase in RPF without a concurrent rise in GFR was produced with dopamine. This was effectively blocked by the peripheral dopamine inhibitor, bulbocapnine.

The D&amp;T report

The D&amp;T report

Sleep Restriction during Pregnancy: Hypertension and Renal Abnormalities in Young Offspring Rats

Because the maternal environment can affect several physiological functions of the newborn, the aim of the present study was to examine the impact of sleep restriction during pregnancy on renal morphology and function in young offspring. Female 3-month-old Wistar rats were divided in 2 experimental groups: C (control) and SR (sleep restriction between the 14th and 20th day of pregnancy). Pregnancy was confirmed by vaginal smear. SR females were subjected to sleep restriction by the multiple platform technique for 20 h daily. After birth, only male litters (6 for each mother) were selected and designated OC (offspring from C) and OSR (offspring from SR). At 2 months of age, blood pressure (BP) was measured by tail plethysmography; at 3 months the renal plasma flow (RPF), glomerular filtration rate (GFR), glomerular area, and number of glomeruli per mm3 were evaluated. Offspring from SR had higher systolic blood pressure than OC. In this group (OSR), we also observed significant increase in RPF and GFR, enlarged glomeruli diameter, and reduced number of glomeruli per mm3 of renal tissue. Our data suggest that sleep restriction during pregnancy is able to modify renal development, resulting in morphologic and functional alterations in young offspring.

Renal and cardio-protective effects of direct renin inhibition: a systematic literature review

Blockade of the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step by means of renin inhibition has led to the development of direct renin inhibitors (DRIs). Given the renal and cardioprotective effects of RAAS blockade by angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, DRIs may increase the armamentarium for further organ protection. Over the last two decades the effects of DRIs on biomarkers for renal and cardiovascular disease have been investigated. This systematic review aims to delineate the effects of DRIs on surrogate markers of renal and cardiovascular function. MEDLINE and previous systematic reviews were searched for articles reported between 1980 and 2008. A standardized dataset was extracted from articles describing the effects of DRIs on markers of renal and cardiac damage and hard outcomes. Fifty-two articles were included. Blood pressure reductions were generally insufficient using early generation DRIs. However, recent DRIs have greater blood pressure-lowering effects. Preclinical and clinical studies showed profound effects of DRIs on markers of renal function, including clear increases in renal plasma flow and reductions in albuminuria. These effects were observed either alone or in combination with other RAAS inhibitors and suggest potential large renal protective benefit. DRIs improved hemodynamic cardiovascular parameters, such as total peripheral resistance, arterial pressure and left ventricular mass index, to a similar extent as those observed with other RAAS inhibitors. Furthermore, addition of DRIs to optimal heart failure treatment resulted in further reductions in B-type natriuretic peptide. Evidence from preclinical and clinical studies suggests that DRIs may have renal and cardiovascular effects beyond their ability to lower blood pressure. Results of ongoing hard outcome trials are awaited to definitively assess the renal and cardio-protective effects of these agents.