Decrease In Renal Blood Flow Research Articles

Purinoreceptor-mediated current in myocytes from renal resistance arteries.

Ionotropic purinoreceptors (P2X) in renal vascular smooth muscle cells (RVSMCs) are involved in mediating the sympathetic control and paracrine regulation of renal blood flow (RBF). Activation of P2X receptors elevates [Ca(2+)](i) in RVSMCs triggering their contraction, leading to renal vasoconstriction and decrease of RBF. The goal of the present work was to characterize the P2X receptor-mediated ionic current (I(P2X)) and to identify the types of P2X receptors expressed in myocytes isolated from interlobar and arcuate arteries of rat kidney. The expression of P2X receptors in isolated RVSMCs was analysed by reverse transcription (RT)-PCR. I(P2X) and membrane potential were recorded using the amphotericin B-perforated patch method. RT-PCR analysis on single RVSMCs showed the presence of genes encoding P2X1 and P2X4 receptors. Under voltage clamp conditions, the selective P2X receptor agonist alphabeta-methylene ATP (alphabeta-meATP) evoked I(P2X) similar to that induced by ATP. Under current clamp conditions, both ATP and alphabeta-meATP evoked a spike-like membrane depolarization followed by a sustained depolarization, linking P2X receptors in RVSMCs to sympathetic control of renal vascular tone. A selective antagonist of P2X1 receptors, NF279, reduced I(P2X) amplitude by approximately 65% concentration-dependently manner within the nanomolar to sub-micromolar range. The residual current was resistant to micromolar concentrations of NF279, but was inhibited by sub-millimolar to millimolar concentrations of NF279. Two types of functional P2X receptors, monomeric P2X1 and heteromeric P2X1/4 receptors, are expressed in RVSMCs. Our study has identified important targets for possible pharmacological intervention in the sympathetic control of renal circulation.

Peroxisome Proliferator-Activated Receptor Alpha and Alpha/Gamma Agonists Do Not Cause Impairment in Renal Function in the Rat

Background/Aims: Patients treated with peroxisome proliferator-activated receptor analogs (PPAR) α or α/γ may develop a transient and reversible increase in serum creatinine, the mechanism of which remains obscure. This study evaluates whether treatment with either PPAR-α or -α/γ analogs, fenofibrate or tesaglitazar, may cause deterioration in renal hemodynamics or exert direct tubular or glomerular nephrotoxic effects in rats. Methods: Male Sprague-Dawley rats (300–320 g) were treated per os with fenofibrate (300 mg/kg/day), tesaglitazar (1.2 mg/kg/day) or vehicle, for 14 days. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by inulin clearance and ultrasonic flowmetry, and cumulative excretion of sodium and creatinine were assessed. Biomarkers of glomerular and tubular injury were measured, including urinary albumin excretion and renal mRNA levels of kidney injury molecule 1 (Kim-1), lipocalin 2 (Lcn2), and osteopontin (Spp1). Results: Fenofibrate and tesaglitazar improved the lipid profile, but caused no detectable decrease in GFR or RBF compared with vehicle-treated rats. Furthermore, the cumulative excretions of sodium and creatinine were not altered by the drugs. Finally, there was no significant difference between drug- and vehicle-treated groups in urinary albumin excretion or in the expression of renal injury biomarkers. Conclusions: In the rat, no direct nephrotoxic effect or deterioration in renal hemodynamics and function were observed following treatment with fenofibrate or tesaglitazar.

P2X1receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

In vitro experiments demonstrate that P2X(1) receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X(1) receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X(1) receptor blockade with IP5I, or A(1) receptor blockade with DPCPX. Both P2X(1) and A(1) receptor stimulation with alpha,beta-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X(1) receptor stimulation. Likewise, administration of DPCPX significantly blocked A(1) receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100-120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80-100 mmHg, suggesting that A(1) receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X(1) receptor activation is important for whole kidney autoregulation in vivo.

Do prostaglandins modulate renal haemodynamic effects of endothelin-1 in conscious lambs?

To test the hypothesis that vasodilatory prostaglandins buffer the renal vasoconstrictor effects of endothelin-1 (ET-1) early in life, renal haemodynamic responses to ET-1 were measured in 2 groups of conscious, chronically instrumented lambs at 1-2 weeks of age (group I, n = 11) and 6 weeks of age (group II, n = 10). Lambs were pretreated with vehicle or 1 mg x kg(-1) indomethacin, a nonselective cyclooxygenase inhibitor, and renal haemodynamic effects were measured continuously for 1 min before (control) and 5 min after intra-arterial injection of 250 ng x kg(-1) ET-1. In group II lambs, there was a marked decrease in renal blood flow (RBF) and renal vascular conductance (RVC) elicited by ET-1 administration, as we have previously described. This response was not altered by vehicle or indomethacin pretreatment. In group I lambs, there was an initial increase but no decrease in RBF and RVC elicited by ET-1 administration, as we have previously described, and this response was also not altered by either vehicle or indomethacin. These results suggest that endogenously produced prostaglandins do not appear to modulate the renal haemodynamic effects of ET-1 in conscious lambs during postnatal maturation.

COMP-Angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury

During sepsis endothelial dysfunction is an important pathogenetic mechanism in acute kidney injury (AKI). Lipopolysaccharide (LPS)-induced endotoxemia is associated with renal hemodynamic changes such as alterations of renal blood flow (RBF), vascular resistance, and glomerular filtration rate. We used adenoviral delivery of an engineered variant of native angiopoietin-1 (COMP-angiopoietin-1) containing anti-inflammatory and anti-permeability functions, to determine if regulation of renal endothelial cell dysfunction may have a beneficial role in preventing AKI during LPS-induced endotoxemia in mice. This treatment prevented the endotoxin-induced decrease of RBF and mean arterial pressure while improving glomerular filtration rate. Treatment also mitigated the effects of LPS on renal intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 protein expression, the number of ER-HR3-positive macrophages that infiltrated the kidney, serum nitrate/nitrite levels, renal inducible nitric oxide synthase protein expression, the induction of tubular epithelial reactive oxygen and nitrogen species, and renal microvascular permeability. Our findings show that COMP-angiopoietin-1, an endothelium-oriented therapeutic agent, protects against AKI caused by endotoxemia.

Bone morphogenic protein-7: a new prognostic marker for acute kidney injury?

Sir, Bone morphogenic protein-7 (BMP-7), also known as osteogenic protein-1 (OP-1), is one of the members of the transforming growth factor s (TGF-s) superfamily [1]. This protein was originally identified as a regulator of cartilage and bone formation. However, BMPs have also been shown to regulate the growth, differentiation and migration of various cell types, including epithelial, mesenchymal, neuronal and haematopoietic cells [2]. Acute kidney injury (AKI)—characterized by a sudden loss of the ability of the kidneys to excrete nitrogenous waste, and to maintain electrolyte and fluid balance—is a frequently encountered clinical problem, especially in the intensive care unit patients. Despite some advances in the management of this condition, unfortunately the morbidity and mortality rates of established AKI still remain high (30–70%) [3]. Acute renal failure occurs as a result of a sudden decrease in renal blood flow, toxic or obstructive insult to the renal tubule or inflammation in the tubulointerstitium. The subsequent dysfunction and loss of tubular epithelial cells is of key importance for the pathophysiological consequences of the syndrome. Contrast-induced nephropathy (CIN) is a distinct type of AKI. Although the pathophysiological processes of CIN are not completely understood, many potential mechanisms for renal injury have been proposed—including contrast-media-induced vasoconstriction resulting in reduction in renal blood flow, direct tubular toxicity and free radical and oxidative injury to tubular cells [4]. Tubular epithelial cells (TECs) are a major source of chemokines, cytokines (such as interleukin-6) and growth factors (such as tumour necrosis factor-α) and they play an important role in the initiation of interstitial inflammation. Furthermore, TECs contribute to the progression of renal fibrosis by undergoing an epithelial–mesenchymal transition (EMT), and leading to accumulation of activated fibroblasts in the interstitium [5]. Several studies showed that the principal target of BMP-7 in the kidney was TECs [6]. It is also demonstrated that BMP-7 decreases the secretion of pro-inflammatory cytokines and growth factors by TECs and reverses epithelial-to-mesenchymal transition, while it acts as an antagonist of TGF-β1-induced E-cadherin downregulation [7,8]. Acute kidney injury associated with tubular necrosis leads to reduction in the expression of tubular BMP-7, and after recovery of tubular and glomerular damage, BMP-7 expression is restored [9]. It is demonstrated that BMP-7 can inhibit EMT involving tubular epithelial cells, resulting in potential repair of injured tubules [8]. Furthermore, administration of exogenous rhBMP-7 accelerates the repair of the injured kidney in animal models [10]. Those findings suggest that BMP-7 plays a critical role in the maintenance of kidney homeostasis [9]. In summary, these data suggest that BMP-7 is an important regulator of the tubular epithelial cell function, inflammatory response and epithelial–mesenchymal transition. Reduced expression of BMP-7 may contribute to the fibrotic response, and its administration may ameliorate renal injury. We speculate that by potential mechanisms of repairing injured tubules, BMP-7 has a critical role in recovery of AKI and it may have a prognostic value. Measuring BMP-7 levels might predict the development of CIN and administering rhBMP-7 to high-risk groups (such as predisposed subjects to CIN, requiring contrast investigations) might prevent the development of CIN. Further studies are necessary to show the exact place of BMP 7 in the recovery period of AKI and whether it might be effective for the treatment of this clinical condition or not, since the mortality and morbidity rates of AKI and CIN are still so high. Conflict of interest statement. None declared.

Mechanisms of Tissue Injury in Renal Artery Stenosis: Ischemia and Beyond

Renal injury distal to an atherosclerotic renovascular obstruction reflects multiple intrinsic factors producing parenchymal tissue injury. Atherosclerotic disease pathways superimposed on renal arterial obstruction may aggravate damage to the kidney and other target organs, and some of the factors activated by renal artery stenosis may in turn accelerate the progression of atherosclerosis. This cross-talk is mediated through amplified activation of renin-angiotensin system, oxidative stress, inflammation, and fibrosis—pathways notoriously involved in renal disease progression. Oxidation of lipids also accelerates the development of fibrosis in the stenotic kidney by amplifying profibrotic mechanisms and disrupting tissue remodeling. The extent to which actual ischemia modulates injury in the stenotic kidney has been controversial, partly because the decrease in renal oxygen consumption usually parallels a decrease in renal blood flow, and because renal vein oxygen pressure in the affected kidney is not decreased. However, recent data using novel methodologies demonstrate that intra-renal oxygenation is heterogeneously affected in different regions of the kidney. Activation of such local injury within the kidney may lead to renal dysfunction and structural injury, and ultimately unfavorable and irreversible renal outcomes. Identification of specific pathways producing progressive renal injury may enable development of targeted interventions to block these pathways and preserve the stenotic kidney.

Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation

Michael R. Charlton, William J. Wall, Akinlolu O. Ojo, Pere Gines, Stephen Textor, Fuad S. Shihab, Paul Marotta, Marcelo Cantarovich, James D. Eason, Russell H. Wiesner, Michael A. Ramsay, Juan C. Garcia-Valdecasas, James M. Neuberger, Sandy Feng, Connie L. Davis, Thomas A. Gonwa, and the International Liver Transplantation Society Expert Panel Mayo Clinic, Rochester MN; Department of General Surgery, London Health Science Center, London, Ontario, Canada; Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain; Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT; Medical School, University of Western Ontario, London, Ontario, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada; Transplant Institute, University of Tennessee, Memphis, TN; Baylor University Medical Center, Dallas, TX; Hospital Clinic I Provincial, Barcelona, Spain; Queen Elizabeth Hospital, Birmingham, England; Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA; Department of Medicine, University of Washington Medical Center, Seattle, WA; and Mayo Clinic, Jacksonville, FL

Blood pressure and renal blow flow responses in heme oxygenase-2 knockout mice

Heme oxygenase (HO) is the enzyme responsible for the breakdown of heme-generating carbon monoxide (CO) and biliverdin in this process. HO-2 is the constitutively expressed isoform in most tissues, such as the kidney and vasculature. CO generated by HO is believed to be an important vasodilator in the renal circulation along with another gas, nitric oxide (NO). To determine the importance of HO-2 in the regulation of blood pressure and renal blood flow (RBF), we treated HO-2 knockout (KO) mice chronically with either ANG II or N(G)-nitroarginine methyl ester (l-NAME). Basal blood pressures were not different between wild-type (WT), heterozygous (HET), or KO mice and averaged 113 +/- 3 vs. 115 +/- 2 vs. 116 +/- 2 mmHg. Similar increases in blood pressure to chronic ANG II as well as l-NAME treatment were observed in all groups with blood pressures increasing an average of 30 mmHg in response to ANG II and 15 mmHg in response to l-NAME. Basal RBFs were not different between the groups averaging 6.0 +/- 0.5 (n = 6) vs. 4.8 +/- 0.6 (n = 10) vs. 5.8 +/- 0.7 (n = 6) ml*min(-1)*g(-1) kidney weight in WT, HET, and KO mice. HO-2 KO and HET mice exhibited an attenuated decrease in RBF in response to acute administration of ANG II, while no differences were observed with l-NAME. Our data indicate that blood pressure and RBF responses to increased ANG II or inhibition of nitric oxide are not significantly enhanced in HO-2 KO mice.

Acute Trypanosoma cruzi experimental infection induced renal ischemic/reperfusion lesion in mice

Experimental acute infection with Trypanosoma cruzi in mice promotes an intense myocarditis and other systemic changes. However, the network of pathophysiological disorders and renal injury caused by the infection has not been elucidated. Our previous results with a murine model observed a discrete acute myocarditis and high mortality with significant inflammatory kidney injury with T. cruzi infection. The aim of this study was to investigate the mechanisms of kidney injury caused by the parasite in mice during the experimental acute phase. Results employing BALB/c mice infected with T. cruzi of Y strain showed renal injury on the 6th day postinfection (dpi) caused by a transitory decrease of renal blood flow. Acute kidney injury (AKI) was also observed similar to the model of ischemia/reperfusion lesion in these infected mice. The injury was not related to the presence (or multiplication) of parasites. Only rare nests were microscopically detected, and the presence of scattered parasites in renal parenchyma was seen on the 15th dpi. Thus, it was observed that during the acute phase of the disease, AKI in infected mice is linked to early cardiovascular effects, including heart failure, caused by striking inflammatory lesions in the myocardium, which lead to the high mortality rate of animals.

Recovery from renal ischemia-reperfusion injury is associated with altered renal hemodynamics, blunted pressure natriuresis, and sodium-sensitive hypertension.

The present studies evaluated intrarenal hemodynamics, pressure natriuresis, and arterial blood pressure in rats following recovery from renal ischemia-reperfusion (I/R) injury. Acute I/R injury, induced by 40 min of bilateral renal arterial occlusion, resulted in an increase in plasma creatinine that resolved within a week. Following 5 wk of recovery on a 0.4% NaCl diet, the pressure-natriuresis response was assessed in anesthetized rats in which the kidney was denervated and extrarenal hormones were administered intravenously. Increasing renal perfusion pressure (RPP) from 107 to 141 mmHg resulted in a fourfold increase in urine flow and sodium excretion in sham control rats. In comparison, pressure diuresis and natriuresis were significantly attenuated in post-I/R rats. In sham rats, glomerular filtration rate (GFR) averaged 1.6 +/- 0.2 mlxmin(-1)xg kidney weight(-1) and renal blood flow (RBF) averaged 7.8 +/- 0.7 mlxmin(-1)xg kidney weight(-1) at RPP of 129 mmHg. Renal cortical blood flow, measured by laser-Doppler flowmetry, was well autoregulated whereas medullary blood flow and renal interstitial hydrostatic pressure increased directly with elevated RPP in sham rats. In contrast, GFR and RBF were significantly reduced whereas medullary perfusion and interstitial pressure demonstrated an attenuated response to RPP in post-I/R rats. Further experiments demonstrated that conscious I/R rats develop hypertension when sodium intake is increased. The present data indicate that the pressure-natriuretic-diuretic response in I/R rats is blunted because of a decrease in GFR and RBF and the depressed pressure-dependent increase in medullary blood flow and interstitial pressure.

Repeated administration of ET B receptor agonist, IRL-1620, produces tachyphylaxis only to its hypotensive effect

IRL-1620, a highly selective ET B receptor agonist, is presently in a phase I clinical trial ( NCT00613691) in the United States for patients with recurrent or progressive carcinoma. The effect of acute repeated administration of IRL-1620 on the development of tachyphylaxis to changes in blood pressure, heart rate and blood flow (renal and cerebral) has not been studied. The present studies were conducted in urethane anesthetized rats to determine the cardiovascular effects of acute repeated intravenous administration of IRL-1620. In order to determine the tachyphylactic effect, each dose of IRL-1620 was administered at 0, 60, and 120 min. It was found that IRL-1620 did not significantly affect heart rate. IRL-1620 produced a transient fall in blood pressure. A fall in mean arterial pressure (MAP) of 35.47% with 1.6 μg/kg, 38.87% with 5.0 μg/kg and 28.04% with 15.0 μg/kg dose of IRL-1620 was observed. Repeated administration of a low dose (1.6 μg/kg, i.v.) of IRL-1620 produced a fall in MAP but no tachyphylaxis was observed. However, repeated administration of IRL-1620 (5.0 μg/kg, i.v.) produced a fall in MAP of 40.12%, 29.15%, and 21.61% with the first, second and third injections, respectively. IRL-1620 produced a consistent decrease in renal blood flow and increase in cerebral blood flow without any evidence of tachyphylaxis. Pretreatment with ET A antagonist BMS187824 (5 mg/kg, i.v.), followed by three doses of 5 μg/kg IRL-1620 at 60 min intervals eliminated the development of tachyphylaxis to the transient hypotension, confirming the involvement of the ET A receptor in tachyphylactic development. The findings indicate development of tachyphylaxis to IRL-1620 only to the fall in blood pressure when given repeatedly at mid-high doses, while the decrease in renal and increase in cerebral blood flow were not affected with regards to tachyphylactic development.

Low‐dose vasopressin increases glomerular filtration rate, but impairs renal oxygenation in post‐cardiac surgery patients

The beneficial effects of vasopressin on diuresis and creatinine clearance have been demonstrated when used as an additional/alternative therapy in catecholamine-dependent vasodilatory shock. A detailed analysis of the effects of vasopressin on renal perfusion, glomerular filtration, excretory function and oxygenation in man is, however, lacking. The objective of this pharmacodynamic study was to evaluate the effects of low to moderate doses of vasopressin on renal blood flow (RBF), glomerular filtration rate (GFR), renal oxygen consumption (RVO2) and renal oxygen extraction (RO2Ex) in post-cardiac surgery patients. Twelve patients were studied during sedation and mechanical ventilation after cardiac surgery. Vasopressin was sequentially infused at 1.2, 2.4 and 4.8 U/h. At each infusion rate, systemic haemodynamics were evaluated by a pulmonary artery catheter, and RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of 51chromium-ethylenediaminetetraacetic acid, respectively. RVO2 and RO2Ex were calculated by arterial and renal vein blood samples. The mean arterial pressure was not affected by vasopressin while cardiac output and heart rate decreased. RBF decreased and GFR, filtration fraction, sodium reabsorption, RVO2, RO2Ex and renal vascular resistance increased dose-dependently with vasopressin. Vasopressin exerted direct antidiuretic and antinatriuretic effects. Short-term infusion of low to moderate, non-hypertensive doses of vasopressin induced a post-glomerular renal vasoconstriction with a decrease in RBF and an increase in GFR in post-cardiac surgery patients. This was accompanied by an increase in RVO2, as a consequence of the increases in the filtered tubular load of sodium. Finally, vasopressin impaired the renal oxygen demand/supply relationship.

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Successful Management of Respiratory Failure Can Improve Renal Function

A subset of patients with acute exacerbation of chronic pulmonary disease present with concomitant acute renal failure (ARF). Acute hypercapnia remains an underappreciated and often overlooked cause of ARF in these patients with acute hypercapnic respiratory failure (AHRF). A nephrology consultation is requested for oliguric ARF in a woman with obesity-hypoventilation syndrome who has been admitted for AHRF and was treated with non-invasive ventilation. Despite stable hemodynamic status, the patient receives a large volume of intravenous fluids in an attempt to improve the renal function and urine output, and develops pulmonary edema and worsening respiratory status.The decision is made to hemodialyze the patient for pulmonary edema and resistant hyperkalemia. However, prior to initiation of hemodialysis, the patient is intubated and started on mechanical ventilation because of progressively worsening respiratory status. This is followed by rapid improvement in hypercapnia and acidosis, and then by a significant increase in urine output. The patient’s renal function and hyperkalemia improves over the next few hours, obviating the need for renal replacement therapy.The potential causes of ARF in patients with AHRF are numerous, and include hemodynamic instability and hypotension, intravascular volume depletion (due to increased insensible loss), concomitant use of medications that affect renal hemodynamics (eg, angiotensin-converting enzyme-I and diuretics), presence of comorbidities with potential impact on renal function (eg, chronic kidney disease, diabetes, heart failure), and interventions performed at the time of admission (eg, intravenous contrast studies and nephrotoxic medications).Management of AHRF frequently parallels the conservative treatment of ARF in these patients, which very often includes administration of large volumes of intravenous fluids with the assumption that the patient is intravascularly volume-depleted. This approach is certainly indicated in patients with hemodynamic instability as well as in those with evidence of intravascular volume depletion and organ hypoperfusion. However, unnecessary and injudicious administration of a large volume of intravenous fluids can result in severe volume overload and worsening respiratory status in other patients.In this regard, it is important to emphasize the role of acute hypercapnia as a potential cause of ARF in patients presenting with AHRF. Although chronically hypercapnic subjects (eg, those with stable chronic obstructive pulmonary disease) have a baseline renovascular resistance similar to normocapnic patients, acute increase in serum CO2 levels is shown to be associated with renal vasoconstriction.1,2 This impact on renal vascular tone is believed to be both direct and indirect (ie, via the sympathetic nervous system).3,4 Vasoconstriction leads to a decrease in renal blood flow and intra-glomerular pressure, with subsequent reduction in glomerular filtration rate. Therefore, it is not unexpected to observe ARF, with pre-renal characteristics without intracascular volume depletion, in patients presenting with AHRF. This physiological concept is further supported by clinical observations such as the one mentioned earlier, in which renal function is improved after successful management of hypercapnia with no additional kidney-oriented intervention.It therefore seems prudent to focus on management of AHRF in patients who present simultaneously with AHRF and ARF. Unnecessary administration of large volumes of intravenous fluids should be avoided in patients without evidence of intravascular volume depletion, and renal replacement therapy can be deferred, if possible, because resolution of AHRF and hypercapnia is typically followed by improvement in renal function.

Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury

Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney.

Renal endothelial function and blood flow predict the individual susceptibility to adriamycin-induced renal damage

Susceptibility to renal injury varies among individuals. Previously, we found that individual endothelial function of healthy renal arteries in vitro predicted severity of renal damage after 5/6 nephrectomy. Here we hypothesized that individual differences in endothelial function in vitro and renal perfusion in vivo predict the severity of renal damage in a model of adriamycin-induced nephropathy. In three separate studies, the following baseline parameters were measured in healthy male Wistar rats: (1) acetylcholine (ACh)-induced relaxation in small renal arteries in vitro (n = 16) and the contribution of prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarizing factor (EDHF) to the relaxation; (2) glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in spontaneously voiding rats in vivo (n = 16) and (3) the acute effect of the NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME, n = 12) on renal blood flow (RBF) as compared to vehicle infusion (n = 9). Following these measurements, adriamycin (1.75 mg/kg i.v.) was injected and subsequent renal damage after 6 weeks was related to the baseline parameters. Total ACh-induced (r = 0.51, P < 0.05) and EDHF-mediated relaxation (r = 0.68, P < 0.05), as well as ERPF (r = 0.66, P < 0.01), positively correlated with the severity of proteinuria 6 weeks after injection. In contrast, pronounced baseline NO-mediated dilation was associated with lower proteinuria (r = 0.71, P < 0.01). Nevertheless, an acute L-NAME infusion, strongly reducing RBF by 22 +/- 8%, during adriamycin administration provided protection against the development of proteinuria. Individual animals with pronounced baseline endothelial dilatory ability measured in vitro and high ERPF in vivo are vulnerable to renal damage after the adriamycin injection. Acute inhibition of NO during adriamycin administration, resulting in a decrease of RBF, protects against renal injury, probably by limiting the delivery of the drug to the kidney. Therefore, interindividual variability in renal haemodynamics might be crucially involved in susceptibility to nephrotoxic renal damage.

Regional decreases in renal oxygenation during graded acute renal arterial stenosis: a case for renal ischemia

Ischemic nephropathy describes progressive renal failure, defined by significantly reduced glomerular filtration rate, and may be due to renal artery stenosis (RAS), a narrowing of the renal artery. It is unclear whether ischemia is present during RAS since a decrease in renal blood flow (RBF), O(2) delivery, and O(2) consumption occurs. The present study tests the hypothesis that despite proportional changes in whole kidney O(2) delivery and consumption, acute progressive RAS leads to decreases in regional renal tissue O(2). Unilateral acute RAS was induced in eight pigs with an extravascular cuff. RBF was measured with an ultrasound flow probe. Cortical and medullary tissue oxygen (P(t(O(2)))) of the stenotic kidney was measured continuously with sensors during baseline, three sequentially graded decreases in RBF, and recovery. O(2) consumption decreased proportionally to O(2) delivery during the graded stenosis (19 +/- 10.8, 48.2 +/- 9.1, 58.9 +/- 4.7 vs. 15.1 +/- 5, 35.4 +/- 3.5, 57 +/- 2.3%, respectively) while arterial venous O(2) differences were unchanged. Acute RAS produced a sharp reduction in O(2) efficiency for sodium reabsorption (P < 0.01). Cortical (P(t(O(2)))) decreases are exceeded by medullary decreases during stenosis (34.8 +/- 1.3%). Decreases in tissue oxygenation, more pronounced in the medulla than the cortex, occur despite proportional reductions in O(2) delivery and consumption. This demonstrates for the first time that hypoxia is present in the early stages of RAS and suggests a role for hypoxia in the pathophysiology of this disease. Furthermore, the notion that arteriovenous shunting and increased stoichiometric energy requirements are potential contributors toward ensuing hypoxia with graded and progressive acute RAS cannot be excluded.

Tumor necrosis factor-α induces renal vasoconstriction as well as natriuresis in mice

Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effects of TNF-α on renal hemodynamic and excretory function are not yet clearly defined. We examined the renal responses to infusion of TNF-α (0.33 ng·g−1·min−1) in anesthetized mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. The urine was collected from a cannula inserted into the bladder. Following the 60-min control clearance period, TNF-α infusion was initiated and 15 min were given for stabilization followed by another 60-min clearance period. TNF-α alone (n = 7) caused decreases in RBF (7.9 ± 0.3 to 6.4 ± 0.3 ml·min−1·g−1) and GFR (1.04 ± 0.06 to 0.62 ± 0.08 ml·min−1·g−1) as well as increases in absolute (0.8 ± 0.3 to 1.4 ± 0.3 μmol·min−1·g−1) and fractional excretion of sodium (0.5 ± 0.2 to 1.5 ± 0.4%) without affecting arterial pressure. TNF-α also increased 8-isoprostane excretion (8.10 ± 1.09 to 11.13 ± 1.34 pg·min−1·g−1). Pretreatment with TNF-α blocker etanercept (5 mg/kg sc; 24 and 3 h before TNF-α infusion; n = 6) abolished these responses. However, TNF-α induced an increase in RBF and caused attenuation of the GFR reduction in mice pretreated with superoxide (O2−) scavenger tempol (2 μg·g−1·min−1; n = 6). Pretreatment with nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (0.1 μg·g−1·min−1; n = 6) resulted in further enhancement in vasoconstriction while natriuresis remained unaffected in response to TNF-α. These data suggest that TNF-α induces renal vasoconstriction and hypofiltration via enhancing the activity of O2− and thus reducing the activity of NO. The natriuretic response to TNF-α is related to its direct effects on tubular sodium reabsorption.

ヨード造影剤による腎障害発現機序の解明とベラプロストの保護作用

Radiocontrast nephropathy (RCN) is a major complication after radiographical examination with iodinated contrast media (CM). Although little is known about the mechanism of RCN, a direct toxic action on renal cells and/or decrease in renal blood flow are considered to be implicated in the pathogenesis of the disease/the condition, A large number of vasodilatory agents, including endothelin antagonists, adenosine antagonists, atrial natriuretic peptide, calcium channel blockers, dopamine, dopamine D1 receptor agonist fenoldopam, and prostaglandin E1 have been tried clinically to prevent RCN, however, most of them have failed. Although prophylactic effects of antioxidant N-acetylcysteine have recently been reported by several investigators, only hydration is a universally accepted protocol to prevent it. In our recent in vitro and in vivo study, we have elucidated that CM induced apoptosis of renal tubular cells through the reduction in Bcl-2 expression and the subsequent activation of caspase-9 and caspase-3. Moreover, we found that CM caused an increase in ceramide content in renal tubular cells, which leads to apoptosis by inhibiting the phosphorylation of Akt and cAMP responsive element binding protein (CREB) and the subsequent reduction in Bcl-2 expression. The inhibitor of ceramide synthase, fumonisin B1, reversed both the elevation of ceramide content and renal cell injury induced by CM. On the other hand, a prostacyclin analog beraprost prevented RCN in mice by the increase of endogenous cAMP and subsequent CREB phosphorylation resulted in enhancement of Bcl-2 expression. These findings suggest that ceramide synthesis inhibitor or beraprost is potentially useful for the prophylaxis of RCN.