Gender-Specific Renoprotective Pathways in αMUPA Transgenic Mice Subjected to Acute Kidney Injury.

Acute kidney injury (AKI) is a serious health concern with high morbidity and high mortality worldwide. Recently, sexual dimorphism has become increasingly recognized as a factor influencing the severity of the disease. This study explores the gender-specific renoprotective pathways in αMUPA transgenic mice subjected to AKI. αMUPA transgenic male and female mice were subjected to ischemia-reperfusion (I/R)-AKI in the presence or absence of orchiectomy, oophorectomy, and L-NAME administration. Blood samples and kidneys were harvested 48 h following AKI for the biomarkers of kidney function, renal injury, inflammatory response and intracellular pathway sensing of or responding to AKI. Our findings show differing responses to AKI, where female αMUPA mice were remarkably protected against AKI as compared with males, as was evident by the lower SCr and BUN, normal renal histologically and attenuated expression of NGAL and KIM-1. Moreover, αMUPA females did not show a significant change in the renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Interestingly, oophorectomized females eliminated the observed resistance to renal injury, highlighting the central protective role of estrogen. Correspondingly, orchiectomy in αMUPA males mitigated their sensitivity to renal damage, thereby emphasizing the devastating effects of testosterone. Additionally, treatment with L-NAME proved to have significant deleterious impacts on the renal protective mediators, thereby underscoring the involvement of eNOS. In conclusion, gender-specific differences in the response to AKI in αMUPA mice include multifaceted and keen interactions between the sex hormones and key biochemical mediators (such as estrogen, testosterone and eNOS). These novel findings shed light on the renoprotective pathways and mechanisms, which may pave the way for development of therapeutic interventions.

Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure.

Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na+ excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

Increased Intra-abdominal Pressure Induces Acute Kidney Injury in an Experimental Model of Congestive Heart Failure.

BACKGROUND: Congestive heart failure (CHF) entails a complex interaction between the heart and the kidney that represents a clinical entity called cardiorenal syndrome (CRS). One of the mechanisms underlying CRS includes increased intra-abdominal pressure (IAP). We examined the effect of elevated IAP on kidney function in rats with low- and high-output CHF. METHODS AND RESULTS: Rats with compensated and decompensated CHF induced by means of aortocaval fistula, rats with myocardial infraction (MI) induced by means of left anterior descending artery ligation, and sham control rats were subjected to either 10 or 14 mm Hg IAP. Urine flow (V), Na+ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pretreatment with tadalafil (10 mg/kg orally for 4 days) on the adverse renal effects of IAP were examined in decompensated CHF and MI. Basal V and GFR were significantly lower in rats with decompensated CHF compared with sham control rats. Decompensated CHF rats and MI rats subjected to 10 and 14 mm Hg IAP exhibited more significant declines in V, UNaV, GFR and RPF than compensated and sham controls. Elevated IAP also induced tubular injury, as evidenced by significantly increased absolute urinary excretion of neutrophil gelatinase-associated lipocalin. In addition, in a nonquantitative histologic analysis, elevated IAP was associated with increase in necrosis and cell shedding to the tubule lumens, especially in the decompensated CHF subgroup. Pretreatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. CONCLUSIONS: Elevated IAP contributes to kidney dysfunction in high- and low-cardiac output CHF. IAP induces both hemodynamic alterations and renal tubular dysfunction. These deleterious effects are potentially reversible and can be ameliorated with the use of phosphodiesterase-5 inhibition.

Nephroprotective effects of TVP1022, a non-MAO inhibitor S-isomer of rasagiline, in an experimental model of diabetic renal ischemic injury.

Ischemic acute kidney injury (iAKI) in diabetes mellitus is associated with a rapid deterioration of kidney function, more than in nondiabetic subjects. TVP1022, a non-MAO inhibitor S-isomer of rasagiline, possesses antioxidative and antiapoptotic activities. The current study examines the effects of TVP1022 and tempol on iAKI in diabetic rats. Diabetes was induced by streptozotocin. iAKI was induced by clamping the left renal artery for 30 min in both diabetic and nondiabetic rats. The right intact kidney served as a control. Forty-eight hours following ischemia, urinary flow (V), sodium excretion (UNaV), and glomerular filtration rate (GFR) in both ischemic and nonischemic kidneys were determined. The nephroprotective effects of tempol and TVP1022 were examined in these rats. Hematoxylin and eosin staining, 4-hydroxynonenal (4-HNE) immunofluorescence, and nitrotyrosine immunohistochemistry were performed on renal tissues of the various experimental groups. Compared with normoglycemic rats, iAKI in diabetic animals caused more profound reductions in V, UNaV, and GFR. Tempol and TVP1022 treatment increased GFR two- and four-fold in diabetic ischemic kidney, respectively. Besides hemodynamic perturbations, iAKI markedly increased renal immunoreactive 4-HNE and nitrotyrosine staining in both diabetic and nondiabetic rats. Moreover, iAKI increased medullary necrosis, congestion, and casts. Noteworthy, these increases were to a larger extent in ischemic diabetic kidneys. TVP1022, and to a lesser extent tempol, decreased nitrotyrosine and 4-HNE immunoreactivities and necrosis and cast formation in the renal medulla. TVP1022 treatment improves renal dysfunction and histological changes in an iAKI diabetic model and suggests a role for TVP1022 therapy in kidney injury.

Restoration of renal responsiveness to atrial natriuretic peptide in experimental nephrotic syndrome by albumin infusion.

BACKGROUND: The natriuretic/diuretic response to atrial natriuretic peptide (ANP), an important regulator of water and Na(+) balance, is markedly attenuated in nephrotic syndrome (NS). It has been suggested that the diminished renal responsiveness to ANP may contribute to the pathogenesis of salt retention and edema formation in NS. However, the mechanisms underlying the renal hyporesponsiveness to ANP remain largely unknown. METHODS: The acute effects of exogenous infusion of ANP (5 µg/kg + 10 µg/kg/h) were studied by clearance methodology in control rats, hypoalbuminemic rats with Adriamycin (ADR)-induced NS and in ADR-treated rats infused with hyperoncotic albumin sufficient to restore plasma albumin to normal levels. RESULTS: Administration of ANP to control rats resulted in a significant increase in urinary flow rate, absolute rate of sodium excretion (+456%) and glomerular filtration rate (GFR). Mean arterial blood pressure decreased following infusion of the peptide. In the nephrotic rats, baseline GFR and Na(+) excretion were significantly lower than in the control animals, and the renal effects of ANP were markedly blunt compared to the control animals. In contrast, the hypotensive effect of ANP in the ADR-treated rats was largely preserved. Infusion of hyperoncotic albumin prior to ANP administration reversed the decrease in baseline GFR and Na(+) excretion and completely restored the renal effects of ANP in the nephrotic rats. CONCLUSION: These findings indicate that renal hyporesponsiveness to ANP in rats with ADR-induced NS is a reversible phenomenon that appears to be of functional origin rather than reflecting permanent cellular damage.

Acute obstructive jaundice and chronic cirrhosis protect against the adverse renal effects of pneumoperitoneum: role of nitric oxide.

BACKGROUND: Obstructive jaundice and cirrhosis are associated with impaired renal function. Previously we demonstrated that increased intra-abdominal pressure (IAP, pneumoperitoneum) in normal rats induced renal dysfunction. This study investigated the renal effects of pneumoperitoneum in rats with acute jaundice and cirrhotic rats. METHODS: Following a baseline period, rats with obstructive jaundice or cirrhosis induced by acute or chronic bile duct ligation (BDL), respectively, and their sham-controls were subjected to consecutive IAPs of 10 and 14 mmHg for 45 min each. Urine flow (V), Na(+) excretion (UNaV), glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary NO metabolites ([Formula: see text]) and cGMP (UcGMP) were determined. RESULTS: Elevating IAP from 0 to 10 and 14 mmHg in normal rats caused IAP-dependent reductions in V, UNaV, GFR, RPF, [Formula: see text] and UcGMP. Basal renal function and hemodynamics were lower in rats with obstructive jaundice. In contrast to normal rats, application of elevated IAP of 10 and 14 mmHg significantly improved V, UNaV, GFR, RPF, and MAP along with increased [Formula: see text] and preserved UcGMP. Similarly, when identical IAP conditions were applied to cirrhotic rats, no deleterious changes in V, UNaV, GFR or RPF were observed. CONCLUSIONS: Application of pneumoperitoneum to rats with acute BDL improves kidney function and renal hemodynamics. Likewise, increased IAP does not exert adverse renal effects in cirrhotic rats. These effects are distinct from the deleterious renal consequences of increased IAP in normal rats. Perturbations in the generation of NO/cGMP during IAP in normal rats but not in rats with BDL or cirrhosis may contribute to these differences.

The Protective Pathways Activated in Kidneys of αMUPA Transgenic Mice Following Ischemia\Reperfusion-Induced Acute Kidney Injury.

Despite the high prevalence of acute kidney injury (AKI), the therapeutic approaches for AKI are disappointing. This deficiency stems from the poor understanding of the pathogenesis of AKI. Recent studies demonstrate that αMUPA, alpha murine urokinase-type plasminogen activator (uPA) transgenic mice, display a cardioprotective pathway following myocardial ischemia. We hypothesize that these mice also possess protective renal pathways. Male and female αMUPA mice and their wild type were subjected to 30 min of bilateral ischemic AKI. Blood samples and kidneys were harvested 48 h following AKI for biomarkers of kidney function, renal injury, inflammatory response, and intracellular pathways sensing or responding to AKI. αMUPA mice, especially females, exhibited attenuated renal damage in response to AKI, as was evident from lower SCr and BUN, normal renal histology, and attenuated expression of NGAL and KIM-1. Notably, αMUPA females did not show a significant change in renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Moreover, αMUPA female mice exhibited the lowest levels of renal apoptotic and autophagy markers during normal conditions and following AKI. αMUPA mice, especially the females, showed remarkable expression of PGC1α and eNOS following AKI. Furthermore, MUPA mice showed a significant elevation in renal leptin expression before and following AKI. Pretreatment of αMUPA with leptin-neutralizing antibodies prior to AKI abolished their resistance to AKI. Collectively, the kidneys of αMUPA mice, especially those of females, are less susceptible to ischemic I/R injury compared to WT mice, and this is due to nephroprotective actions mediated by the upregulation of leptin, eNOS, ACE2, and PGC1α along with impaired inflammatory, fibrotic, and autophagy processes.

Edema formation in congestive heart failure and the underlying mechanisms.

Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.

Aortocaval fistula in rat: a unique model of volume-overload congestive heart failure and cardiac hypertrophy.

Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy development. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience.

Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy.

During the current formidable COVID-19 pandemic, it is appealing to address ideas that may invoke therapeutic interventions. Clotting disorders are well recognized in patients infected with severe acute respiratory syndrome (SARS) caused by a novel coronavirus (SARS-CoV-2), which lead to severe complications that worsen the prognosis in these subjects. Increasing evidence implicate Heparan sulfate proteoglycans (HSPGs) and Heparanase in various diseases and pathologies, including hypercoagulability states. Moreover, HSPGs and Heparanase are involved in several viral infections, in which they enhance cell entry and release of the viruses. Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod.

Q fever vertebral osteomyelitis among adults: a case series and literature review.

BACKGROUND: Q fever osteoarticular infections are a rare complication of the chronic form of Q fever. We aimed to characterize chronic Q fever vertebral osteomyelitis through our experience and a review of the literature. METHODS: Four adult patients with Q fever vertebral osteomyelitis diagnosed in a tertiary hospital in northern Israel between 2016 to 2020 are described. In addition, a 30 years' literature review of Q fever vertebral osteomyelitis, characterizing predisposing factors, clinical presentation, course of disease, treatment and outcomes, was performed. RESULTS: Thirty-four adult patients with Q fever vertebral osteomyelitis were identified. The vast majority were male (30/34, 88%) with a mean age of 67.2 ± 10 years. Involvement of the adjacent aorta, likely the origin of the infection, was observed in 23/34 (68%) of the patients, usually among patients with aortic graft or aneurysm. Clinical presentation was insidious and fever was frequently absent. Delayed diagnosis for months to years after symptoms onset was frequently reported. Vascular infections were managed with or without extraction of the infected aneurysm/aorta and graft placement. The outcome was variable with limited follow-up data in most cases. Patients were usually treated with prolonged antimicrobial therapy, most commonly doxycycline and hydroxychloroquine combination therapy. CONCLUSION: Q fever should be included in the differential diagnosis of vertebral osteomyelitis in endemic settings, in particular when concomitant adjacent vascular infection exists.

Nitric oxide synthase inhibition aggravates the adverse renal effects of high but not low intraabdominal pressure.

BACKGROUND: Previously, the authors demonstrated that an intraabdominal pressure (IAP) of 14 mmHg in normal rats reduced kidney function/hemodynamics. These adverse effects are related to interference with the nitric oxide (NO) system. This study was designed to compare the effects of NO synthase (NOS) inhibition on kidney function/hemodynamics during increases in IAP from 0 mmHg to 7, 10, and 14 mmHg. METHODS: The rats were divided into six groups. After an IAP of 0 (baseline), the first three groups were subjected to increasing IAPs as follows: 7 mmHg (group 1), 10 mmHg (group 2), and 14 mmHg (group 3). Each pressure was applied for 1 h, followed by a deflation period of 60 min (recovery). An additional three groups were pretreated with nitro-L: -arginine methyl ester (L: -NAME), an NOS inhibitor, before pressures of 7 mmHg (group 4), 10 mmHg (group 5) and 14 mmHg (group 6) were applied for 1 h. Urine flow rate (V), Na(+) excretion (U(Na)V), glomerular filtration rate (GFR), and renal plasma flow (RPF), were determined throughout the experiments. RESULTS: There were no significant changes in V, U(Na)V, GFR, or RPF during 7-mmHg insufflation. However, significant reductions in these parameters were observed during 10 and 14 mmHg, with V decreasing from 9.95 + or - 1.34 microl/min to 6.8 + or - 1.1 and 6.1 + or - 0.5 microl/min (p < 0.05) and U(Na)V decreasing from 1.29 + or - 0.28 to 0.43 + or - 0.32 muEq/min (p < 0.05), and 0.39 + or - 0.09 muEq/min (p < 0.05). These alterations in excretory functions were associated with considerable declines in GFR, from 1.98 + or - 0.2 to 1.05 + or - 0.18 ml/min (p < 0.05) and 0.95 + or - 0.06 ml/min (p < 0.05) and RPF from 8.66 + or - 0.62 to 3.94 + or - 0.88 ml/min (p < 0.05) and 3.08 + or - 0.71 ml/min (p < 0.05), respectively. When the animals were pretreated with L: -NAME, the adverse renal effects of an IAP of 14 mmHg, but not 10 mmHg, were substantially aggravated. CONCLUSION: Decreased renal function/perfusion is induced by IAP pressures of 10 and 14 mmHg but not 7 mmHg. Inhibition of NOS aggravates the adverse renal effects of high (14 mmHg) but not low (7 or 10 mmHg) IAP, indicating that NO deficiency may contribute to the renal dysfunction during high IAP.

The Lung Macrophage in SARS-CoV-2 Infection: A Friend or a Foe?

Respiratory, circulatory, and renal failure are among the gravest features of COVID-19 and are associated with a very high mortality rate. A common denominator of all affected organs is the expression of angiotensin-converting enzyme 2 (ACE2), a protease responsible for the conversion of Angiotensin 1-8 (Ang II) to Angiotensin 1-7 (Ang 1-7). Ang 1-7 acts on these tissues and in other target organs via Mas receptor (MasR), where it exerts beneficial effects, including vasodilation and suppression of inflammation and fibrosis, along an attenuation of cardiac and vascular remodeling. Unfortunately, ACE2 also serves as the binding receptor of SARS viral spike glycoprotein, enabling its attachment to host cells, with subsequent viral internalization and replication. Although numerous reports have linked the devastating organ injuries to viral homing and attachment to organ-specific cells widely expressing ACE2, little attention has been given to ACE-2 expressed by the immune system. Herein we outline potential adverse effects of SARS-CoV2 on macrophages and dendritic cells, key cells of the immune system expressing ACE2. Specifically, we propose a new hypothesis that, while macrophages play an important role in antiviral defense mechanisms, in the case of SARS-CoV, they may also serve as a Trojan horse, enabling viral anchoring specifically within the pulmonary parenchyma. It is tempting to assume that diverse expression of ACE2 in macrophages among individuals might govern the severity of SARS-CoV-2 infection. Moreover, reallocation of viral-containing macrophages migrating out of the lung to other tissues is theoretically plausible in the context of viral spread with the involvement of other organs.

Multidetector CT angiography in the evaluation of acute mesenteric ischemia.

The aim of this study was to determine the accuracy of multidetector row CT angiography in the diagnosis of acute mesenteric ischemia. Ninety-three consecutive studies on 91 patients with clinically suspected acute mesenteric ischemia underwent abdominal CT angiography as the first, and usually the sole, diagnostic procedure. CT was performed with a multidetector 16-row CT system from the level of the diaphragm to the pelvis in two phases: early arterial and late portal phase. CT examinations were reviewed by the duty radiologist. Final diagnosis was established by a senior radiologist. CTA was diagnostic in 92 studies. Mesenteric ischemia was diagnosed in 18 patients, 14 of them were of the thromboembolic type and four from the nonocclusive type. Positive CTA findings were confirmed by surgery in 13 patients and by clinical follow-up in three cases. Other reasons for abdominal pain were diagnosed by CT in 38 patients out of the remaining 74. There were two false positive and two false negative CT results, resulting in an overall accuracy of 95.6%. Multidetector CT angiography is a fast and accurate investigation for the diagnosis of acute mesenteric ischemia and in most cases can be used as the sole diagnostic procedure.

Urinary excretion of endothelin receptors ET A and ET B in hypertensive patients and normotensive subjects.

BACKGROUND/AIMS: Endothelin (ET)-1 is produced by most renal cell types. Renal tubular and vascular cells express both the ET receptors ET(A) and ET(B). Since significant amounts of ET-1 of renal origin were detected in human urine, urinary ET-1 has been used as an index for the capacity of renal ET-1 production. Here, we determine the existence of additional components of the intrarenal ET system, namely the ET(A) and ET(B) receptor subtypes, in the urine of normal and hypertensive subjects. METHODS: ET(A) and ET(B) receptors were detected in urine samples that were concentrated by TCA precipitation, Speedvac or ProteoSpin. RESULTS: Analysis of the human urine extracts revealed the existence of approximately 50 and 55 kDa of immunoreactive proteins, corresponding to ET(B) and ET(A), respectively, indicating that intact ET(A) and ET(B) are excreted in the urine of healthy subjects and hypertensive patients. Normotensive and hypertensive subjects had statistically comparable ET(B) excretion normalized to creatinine (0.58 +/- 0.16 vs. 0.83 +/- 0.17 microg/mg creatinine, respectively; p = 0.304). In contrast, ET(A) excretion was higher among hypertensive subjects (0.05 +/- 0.01 vs. 0.11 +/- 0.02 microg/mg creatinine; p = 0.0451). Immunostaining of ET(A) and ET(B) in the human urinary system revealed expression of both receptors, principally in tubular cells (mainly in medullary collecting ducts) and in the bladder urothelium, and ET(A) expression in the peritubular capillaries and arterioles. Urinary ET receptors closely and inversely correlated with indices of urine concentration, suggesting that their shedding is principally affected by urine flow. CONCLUSION: ET receptors are present in human urine, conceivably originating within the urinary system. Their excretion is principally affected by urinary concentration. It remains to be determined whether urinary ET(A)/ET(B) is of physiological/pathophysiological relevance.

Impact of pneumoperitoneum on renal perfusion and excretory function: beneficial effects of nitroglycerine.

BACKGROUND: Increased intra-abdominal pressure (IAP) (pneumoperitoneum) during laparoscopic surgery may result in adverse effects on kidney function. The mechanisms underlying this phenomenon have not been fully determined. OBJECTIVE: The present study was designed to: (1) investigate the effects of incremental increases in IAP on renal function in normal rats and (2) evaluate whether the nitric oxide (NO) system is involved in renal dysfunction characterizing pneumoperitoneum. METHODS: Male rats were organized into two groups. The first group was subjected to IAP of 0 (baseline), 7 or 14 mmHg, over 1 h for each pressure, followed by a deflation period of 60 min (recovery). Two additional groups were pretreated with: (1) non-depressor dose of nitroglycerine (NTG) and (2) nitro-L-arginine-methylester (L-NAME), an NO synthase inhibitor, before applying 14 mmHg for 1 h. Urine flow rate (V), Na+ excretion (U(Na)V), glomerular filtration rate (GFR), renal plasma flow (RPF), and blood pressure were determined throughout the experiments. RESULTS: There were no significant changes in V, U(Na)V, GFR, and RPF during 7 mmHg insufflation. However, significant reductions in these parameters were observed during 14 mmHg: V from 8.49 +/- 0.92 to 6.12 +/- 0.54 microl/min, U(Na)V from 1.29 +/- 0.28 to 0.39 +/- 0.09 microEq/min, and FE(Na) from 0.37 +/- 0.11 to 0.27 +/- 0.04%. These alterations in excretory functions were associated with a considerable decline in GFR from 1.85 +/- 0.09 to 0.88 +/- 0.09 ml/min, p < 0.05, (-46.3 +/- 5.2% from baseline) and RPF from 8.66 +/- 0.62 to 4.33 +/- 0.49 ml/min, p < 0.05, (-51.93 +/- 5.24% from baseline), without a significant change in mean arterial blood pressure (MAP). When the animals were pretreated with NTG, the adverse effects of pneumoperitoneum on V, U(Na)V, GFR, and RPF were substantially improved, suggesting that NO system plays a beneficial counter-regulatory role during laparoscopy. In line with this notion, pretreatment with L-NAME remarkably aggravated pneumoperitoneum-induced renal hypoperfusion and dysfunction. CONCLUSION: Decreased renal perfusion and function are induced by IAP pressure of 14 mmHg. These adverse effects are probably related to interference with the NO system, and could be partially ameliorated by pretreatment with NTG.

Effects of novel vasopressin receptor antagonists on renal function and cardiac hypertrophy in rats with experimental congestive heart failure.

Arginine vasopressin (AVP) plays an important role in renal hemodynamic alterations, water retention, and cardiac remodeling in congestive heart failure (CHF). The present study evaluated the acute and chronic effects of vasopressin V(1a) receptor subtype (V(1a)) and vasopressin V(2) receptor subtype (V(2)) antagonists on renal function and cardiac hypertrophy in rats with CHF. The effects of acute administration of SR 49059 [(2S)1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide)] (0.1 mg/kg) and SR 121463B (1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethoxy)cyclohexane]indol-2-one, fumarate; equatorial isomer) (0.3 mg/kg), V(1a) and V(2) antagonists, respectively, on renal function, and of chronic treatment (3.0 mg/kg/day for 7 or 28 days, via osmotic minipumps or p.o.), on water excretion and cardiac hypertrophy were studied in rats with aortocaval fistula and control rats. CHF induction increased plasma AVP (12.8 +/- 2.5 versus 32.2 +/- 8.3 pg/ml, p < 0.05). Intravenous bolus injection of SR 121463B to controls produced dramatic diuretic response (from 5.5 +/- 0.8 to 86.3 +/- 21.9 microl/min; p < 0.01). In contrast, administration of SR 49059 did not affect urine flow. Likewise, administration of SR 121463B, but not SR 49059, to rats with CHF significantly increased urinary flow rate from 20.8 +/- 6.4 to 91.6 +/- 26.5 microl/min (p < 0.01). The diuretic effects of SR 121463B were associated with a significant decline in urinary osmolality and insignificant change of Na+ excretion. In line with its acute effects, chronic administration of SR 121463B to CHF rats increased daily urinary volume 2 to 5-fold throughout the treatment period. Both SR 121463B and SR 49059 significantly reduced heart weight in CHF rats when administered for 4 weeks, but not 1 week. These results suggest that V(2) and V(1a) antagonists improve water balance and cardiac hypertrophy in CHF and might be beneficial for the treatment of water retention and cardiac remodeling in CHF.

Dynamic Autologous Reendothelialization of Small-Caliber Arterial Extracellular Matrix: A Preclinical Large Animal Study.

Effective cellularization is a key approach to prevent small-caliber (<4 mm) tissue-engineered vascular graft (TEVG) failure and maintain patency and contractility following implantation. To achieve this goal, however, improved biomimicking designs and/or relatively long production times (typically several months) are required. We previously reported on porcine carotid artery decellularization yielding biomechanically stable and cell supportive small-caliber (3-4 mm diameter, 5 cm long) arterial extracellular matrix (scaECM) vascular grafts. In this study, we aimed to study the scaECM graft patency in vivo and possibly improve that patency by graft pre-endothelialization with the recipient porcine autologous cells using our previously reported custom-designed dynamic perfusion bioreactor system. Decellularized scaECM vascular grafts were histologically characterized, their immunoreactivity studied in vitro, and their biocompatibility profile evaluated as a xenograft subcutaneous implantation in a mouse model. To study the scaECM cell support and remodeling ability, pig autologous endothelial and smooth muscle cells (SMCs) were seeded and dynamically cultivated within the scaECM lumen and externa/media, respectively. Finally, endothelialized-only scaECMs-hypothesized as a prerequisite for maintaining graft patency and controlling intimal hyperplasia-were transplanted as an interposition carotid artery graft in a porcine model. Graft patency was evaluated through angiography online and endpoint pathological assessment for up to 6 weeks. Our results demonstrate the scaECM-TEVG biocompatibility preserving a structurally and mechanically stable vascular wall not just following decellularization and recellularization but also after implantation. Using our dynamic perfusion bioreactor, we successfully demonstrated the ability of this TEVG to support in vitro recellularization and remodeling by primary autologous endothelial and SMCs, which were seeded on the lumen and the externa/media layers, respectively. Following transplantation, dynamically endothelialized scaECM-TEVGs remained patent for 6 weeks in a pig carotid interposition bypass model. When compared with nonrevitalized control grafts, reendothelialized grafts provided excellent antithrombogenic activity, inhibited intimal hyperplasia formation, and encouraged media wall infiltration and reorganization with recruited host SMCs. We thus demonstrate that readily available decellularized scaECM can be promptly revitalized with autologous cells in a 3-week period before implantation, indicating applicability as a future platform for vascular reconstructive procedures.

Implications of the natriuretic peptide system in the pathogenesis of heart failure: diagnostic and therapeutic importance.

The natriuretic peptide family consists of at least 3 structurally similar peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Under normal conditions, ANP is synthesized by the atrium and released in response to atrial stretch. This peptide plays an important role in sodium and water homeostasis and is involved in cardiovascular function. In contrast, BNP is synthesized primarily by the ventricles, and its circulatory concentrations are significantly elevated in profound congestive heart failure (CHF). While both plasma levels of ANP and BNP have been found to be increased in patients with various heart diseases, the elevation in circulatory BNP correlates better than ANP with the severity of CHF. Therefore, plasma BNP has been suggested (and lately used) to aid in the accurate diagnosis of heart failure in patients admitted to the emergency room with symptoms of decompensated heart failure. Furthermore, circulatory BNP has been utilized as a prognostic marker in CHF as well as a hormone guide in the evaluation of the efficacy of the conventional treatment of this disease state. In light of the cardiovascular and renal effects of BNP, which most likely exceed those of ANP, the former has been used as a therapeutic agent for the treatment of patients with acute severe CHF. Intravenous infusion of BNP into patients with sustained ventricular dysfunction causes a balanced arterial and venous vasodilatation that has been shown to result in rapid reduction in ventricular filling pressure and reversal of heart failure symptoms, such as dyspnea and acute hemodynamic abnormalities. Thus, the goal of this article is to review the physiology and pathophysiology of natriuretic peptides and the potential use of their circulating levels for diagnosis and treatment of heart failure.

Induction of cardiac hypertrophy by a controlled reproducible sutureless aortocaval shunt in the mouse.

Much of the understanding about the pathophysiological responses to chronic cardiac overload has been gained by the use of rat and dog models of aortocaval fistula (ACF). The use of a similar model in genetically manipulated mice may further elucidate the molecular mechanisms in these responses. The only reports about ACF in mice to date have applied a needle puncture to create the ACF, which may result in an uncontrolled and irreproducible size of the shunt, and require several weeks to induce the characteristic cardiac changes. In order to obtain a more consistent approach to characterize this mode of cardiac hyperfunction, we present a surgical murine model of ACF that results in rapid progression of the typical systemic and cardiac changes. A sutureless side-to-side infrarenal surgical anastomosis of 0.6-0.8 mm in diameter was created between the abdominal aorta and inferior vena cava in ICR (Institute of Cancer Research) mice. Six to 7 days later, significant cardiac hypertrophy developed. The heart/body weight ratio increased from 0.45 +/- 0.02% in control mice to 0.77 +/- 0.03% in mice with ACF (p < .003). The dry heart weight ratio increased from 0.099 +/- 0.0033% to 0.13 +/- 0.008% (p < .006). The ACF dramatically induced the atrial and ventricular expression of atrial natriuretic factor mRNA, and increased the total cardiac content of endothelin-1 (162.5 +/- 50.6 vs. 83.9 +/- 9.0 pg). Mean arterial pressure in anesthetized mice with ACF decreased from 69.8 +/- 4.9 to 54.8 +/- 5.5 mm Hg (p < .025). Urinary sodium excretion returned to preoperative levels several days following surgery. These results demonstrate that cardiac hypertrophy could be rapidly and reproducibly achieved in mice by the placement of a surgical ACF. This model, when applied in genetically manipulated mice, may be a valuable tool for functional genomic studies about the pathogenesis of cardiac hypertrophy and heart failure.