Psychotropic drugs upregulate aquaporin-2 via vasopressin-2 receptor/cAMP/protein kinase A signaling in inner medullary collecting duct cells.

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser261.NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser261 and accelerated AQP2 transcription.

Thick ascending limb claudins are altered to increase calciuria and magnesiuria in metabolic acidosis.

Urinary calcium and magnesium wasting is a characteristic feature of metabolic acidosis, and this study focused on the role of the thick ascending limb of Henle's loop in metabolic acidosis-induced hypercalciuria and hypermagnesiuria because thick ascending limb is an important site of paracellular calcium and magnesium reabsorption. Male Sprague-Dawley rats were used to determine the effects of acid loading (by adding NH4Cl, 7.2 mmol/220 g body wt/day to food slurry for 7 days) on renal expression of claudins and then to evaluate whether the results were reversed by antagonizing calcium-sensing receptor (using NPS-2143). At the end of each animal experiment, the kidneys were harvested for immunoblotting, immunofluorescence microscopy, and quantitative PCR (qPCR) analysis of claudins and the calcium-sensing receptor. As expected, NH4Cl loading lowered urinary pH and increased excretion of urinary calcium and magnesium. In NH4Cl-loaded rats, renal protein and mRNA expression of claudin-16, and claudin-19, were decreased compared with controls. However, claudin-14 protein and mRNA increased in NH4Cl-loaded rats. Consistently, the calcium-sensing receptor protein and mRNA were up-regulated in NH4Cl-loaded rats. All these changes were reversed by NPS-2143 coadministration and were confirmed using immunofluorescence microscopy. Hypercalciuria and hypermagnesiuria in NH4Cl-loaded rats were significantly ameliorated by NPS-2143 coadministration as well. We conclude that in metabolic acidosis, claudin-16 and claudin-19 in the thick ascending limb are down-regulated to produce hypercalciuria and hypermagnesiuria via the calcium-sensing receptor.NEW & NOTEWORTHY This study found that the thick ascending limb of Henle's loop is involved in the mechanisms of hypercalciuria and hypermagnesiuria in metabolic acidosis. Specifically, expression of claudin-16/19 and claudin-14 was altered via up-regulation of calcium-sensing receptor in NH4Cl-induced metabolic acidosis. Our novel findings contribute to understanding the regulatory role of paracellular tight junction proteins in the thick ascending limb.

Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477.

Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski's rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.

Association between Left Ventricular Systolic Dysfunction and Mortality in Patients with Septic Shock.

BACKGROUND: The impact of myocardial damage on the prognosis of patients with septic shock is not clearly elucidated because complex hemodynamic changes in sepsis obscure the direct relationship. We evaluated left ventricular (LV) conditions that reflect myocardial damage independently from hemodynamic changes in septic shock and their influence on the prognosis of patients. METHODS: We retrospectively enrolled 208 adult patients who were admitted to the intensive care unit and underwent echocardiography within 7 days from the diagnosis of septic shock. Patients who were previously diagnosed with structural heart disease or coronary artery disease were excluded. Left ventricular ejection fraction (LVEF) was divided into four categories: normal, ≥ 50%; mild, ≥ 40%; moderate, ≥ 30%; and severe dysfunction, < 30%. Wall motion impairment was categorized into the following patterns: normal, diffuse, ballooning, and focal. RESULTS: There were 141 patients with normal LVEF. Among patients with impaired LV wall motion, the diffuse pattern was the most common (34 patients), followed by the ballooning pattern (26 patients). Finally, 102 patients died, and in-hospital mortality was significantly higher in patients with severe LV systolic dysfunction (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.04-3.75; P = 0.039) and in patients with diffuse pattern of LV wall motion impairment (HR, 2.28; 95% CI, 1.19-4.36; P = 0.013) than in those with a normal LV systolic function. CONCLUSION: Severe LV systolic dysfunction and diffuse pattern of LV wall motion impairment significantly affected in-hospital mortality in patients with septic shock. Conventional echocardiographic evaluation provides adequate information on the development of myocardial damage and accurately predicts the prognosis of patients with septic shock.

Prognostic Value of Admission Blood Glucose Level in Critically Ill Patients Admitted to Cardiac Intensive Care Unit according to the Presence or Absence of Diabetes Mellitus.

BACKGROUND: Admission blood glucose (BG) level is a predictor of mortality in critically ill patients with various conditions. However, limited data are available regarding this relationship in critically ill patients with cardiovascular diseases according to diabetic status. METHODS: A total of 1,780 patients (595 with diabetes) who were admitted to cardiac intensive care unit (CICU) were enrolled from a single center registry. Admission BG level was defined as maximal serum glucose level within 24 hours of admission. Patients were divided by admission BG level: group 1 (< 7.8 mmol/L), group 2 (7.8-10.9 mmol/L), group 3 (11.0-16.5 mmol/L), and group 4 (≥ 16.6 mmol/L). RESULTS: A total of 105 patients died in CICU (62 non-diabetic patients [5.2%] and 43 diabetic patients [7.9%]; P = 0.105). The CICU mortality rate increased with admission BG level (1.7%, 4.8%, 10.3%, and 18.8% from group 1 to group 4, respectively; P < 0.001). On multivariable analysis, hypertension, mechanical ventilator, continuous renal replacement therapy, acute physiology and chronic health evaluation II (APACHE II) score, and admission BG level significantly influenced CICU mortality in non-diabetic patients (group 1 vs. group 3: hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.47-7.44; P = 0.004; group 1 vs. group 4: HR, 6.56; 95% CI, 2.76-15.58; P < 0.001). However, in diabetic patients, continuous renal replacement therapy and APACHE II score influenced CICU mortality but not admission BG level. CONCLUSION: Admission BG level was associated with increased CICU mortality in critically ill, non-diabetic patients admitted to CICU but not in diabetic patients.

Tight junction protein expression from peritoneal dialysis Effluent.

Background: We hypothesized that tight junction (TJ) proteins may have a role in paracellular transport of solute and water in peritoneal dialysis (PD) patients. Previous studies on TJ proteins in PD patients have used only cultured human peritoneal mesothelial cells (HPMCs). This study was undertaken to test whether TJ proteins are directly identified from PD effluent and whether their expressions are associated with functional parameters of PD.Methods: Dialysis effluents were collected from 40 patients undergoing PD, after the peritoneal equilibration test (PET). Different molecular sizes of Amicon Ultra-15 Centrifugal Filter Units were used to concentrate and purify proteins in PD effluents, and immunoblot analyses for occludin, ZO-1, and claudins were carried out to test for their existence and relationships with peritoneal clearance or results of the PET.Results: Immunoblotting from PD effluents revealed discrete bands of occludin (∼65 kDa), ZO-1 (∼215 kDa), claudin-1 (∼22 kDa), and claudin-15 (∼22 kDa) in all 40 patients. The peritoneal creatinine clearance inversely correlated with the protein expression of claudin-1 (r= -0.369, p= .019), and the dialysate-to-plasma creatinine ratio at 4 h PET correlated with occludin (r = 0.396, p= .011) and inversely correlated with claudin-15 (r= -0.393, p= .012).Conclusion: In PD patients, expression of peritoneal TJ proteins can be estimated from the dialysis effluent and may be used as novel peritoneal biomarkers.

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy.

BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. METHODS: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. RESULTS: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1ß was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91phox, p47phox, and p67phox in rat kidneys with doxorubicin nephropathy. CONCLUSION: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

Alteration of Tight Junction Protein Expression in Dahl Salt-Sensitive Rat Kidney.

BACKGROUND/AIMS: Altered pressure natriuresis is an important mechanism of hypertension, but it remains elusive at the molecular level. We hypothesized that in the kidney, tight junctions (TJs) may have a role in pressure natriuresis because paracellular NaCl transport affects interstitial hydrostatic pressure. METHODS: To assess the association of salt-sensitive hypertension with altered renal TJ protein expression, Dahl salt-sensitive (SS) and salt-resistant (SR) rats were put on an 8% NaCl-containing rodent diet for 4 weeks. Systolic blood pressure (SBP) and urine NaCl excretion were measured weekly, and kidneys were harvested for immunoblotting and quantitative PCR analysis at the end of the animal experiments. RESULTS: SBP was significantly higher in SS rats than in SR rats during the first to fourth weeks of the animal experiments. During the first and second week, urinary NaCl excretion was significantly lower in SS rats as compared with SR rats. However, the difference between the two groups vanished at the third and fourth weeks. In the kidney, claudin-4 protein and mRNA were significantly increased in SS rats as compared with SR rats. On the other hand, occludin protein and mRNA were significantly decreased in SS rats as compared with SR rats. The expression of claudin-2, claudin-7, and claudin-8 did not vary significantly between the two groups. CONCLUSIONS: In SS rats, SS hypertension was associated with differential changes in renal TJ protein expression. Both upregulation of claudin-4 and downregulation of occludin might increase paracellular NaCl transport in the kidney, resulting in impaired pressure natriuresis in SS rats.

Epicardial adipose tissue is related to cardiac function in elderly women, but not in men.

BACKGROUND AND AIM: Epicardial adipose tissue (EAT) is easily quantifiable visceral adipose tissue that is closely associated with cardiometabolic disease including heart failure with preserved left ventricular (LV) ejection fraction. As body fat distribution and metabolism are different between men and women, we evaluated the sex difference in EAT thickness and its relationship to cardiac function. METHODS AND RESULTS: A total of 152 consecutive patients (76 men) with mean age of 62 ± 9 years were enrolled. Conventional echocardiography was performed and EAT thickness was measured perpendicularly on the right ventricular free wall at end systole. Mean EAT thickness in all patients was 6.5 ± 2.0 mm. EAT thickness was associated with patient age, body mass index, and the presence of hypertension. EAT thickness was not different by sex in patients younger than 60 years (men, 6.4 ± 2.0 mm; women, 6.2 ± 1.8 mm, p = 0.716); however, among patients aged 60 years or older, EAT thickness was significantly greater in women than men (men, 6.0 ± 1.7 mm; women 7.7 ± 2.1 mm, p < 0.001). LV function represented by E/e' and s' was significantly related to EAT thickness only in women (E/e', ß = 0.330, p = 0.002; lateral s', ß = -0.225, p = 0.042). CONCLUSION: EAT thickness was greater in women than men after 60 years old and its relationship with LV function was significant only in women. Greater increase in EAT thickness in elderly women after menopause might partially account for this difference.

Layer-specific dyssynchrony and its relationship to the change of left ventricular function in hypertensive patients.

Left ventricular (LV) remodeling in systemic arterial hypertension causes electrical conduction delay and impairs synchronous contraction, which may contribute to the development of heart failure. This study aimed to assess the change of LV mechanics in hypertension by layer-specific dyssynchrony. One hundred and twenty-one patients with primary hypertension and LV ejection fraction >50 % (mean age, 62 ± 10 years) and 31 normotensive controls (mean age, 63 ± 9 years) were prospectively included. Layer-specific dyssynchrony index (DI) was defined as standard deviation of time interval (TI) from the onset of Q wave to peak longitudinal strain obtained from 18 segments in each endocardial, myocardial, and epicardial layer. The global TI between the onset of Q wave to peak global longitudinal strain in each layer was obtained and the time difference (TD) of global TI between layers was calculated. DIs were significantly different in three layers (P < 0.001 in both groups), and were significantly greater in hypertensive patients than in controls except epicardial DI. End diastolic filling pressure and LV global longitudinal strain were related with endocardial DI. TD between endocardium and myocardium was greater in hypertensive patients than in controls (P = 0.001). Layer-specific DI revealed delayed contraction in each layer and between layers in hypertensive patients, which were apparent in endocardium and between endocardium and myocardium. Increased layer-specific DIs were associated with subclinical LV dysfunction, although LV ejection fraction was preserved. These may be helpful to understand layer-specific mechanical property of LV myocardium and for early detection of subclinical impairment of myocardial function.

Cyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney.

Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4-hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water-loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats. In cyclophosphamide-treated rats, significant increases in renal expression of aquaporin-2 (AQP2) and Na-K-2Cl cotransporter type 2 (NKCC2) were shown by immunoblot analysis and immunohistochemistry. Apical translocation of AQP2 was also demonstrated by quantitative immunocytochemistry. In both rat kidney and primary cultured IMCD cells, significant increases in AQP2 and vasopressin receptor type 2 (V2R) mRNA expression were demonstrated by real-time quantitative PCR analysis. Confocal laser-scanning microscopy revealed that apical translocation of AQP2 was remarkably increased when primary cultured IMCD cells were treated with 4-HC in the absence of vasopressin stimulation. Moreover, AQP2 upregulation and cAMP accumulation in response to 4-HC were significantly reduced by tolvaptan cotreatment in primary cultured IMCD cells and IMCD suspensions, respectively. We demonstrated that, in the rat kidney, cyclophosphamide may activate V2R and induce upregulation of AQP2 in the absence of vasopressin stimulation, suggesting the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD).

Clinical Significance of Dynamic Left Ventricular Outflow Tract Obstruction During Dobutamine Stress Echocardiography in Women With Suspected Coronary Artery Disease.

BACKGROUND: Although dobutamine stress echocardiography (DSE) is frequently associated with dynamic left ventricular outflow tract obstruction (DLVOTO), little is known about its clinical significance in women with suspected coronary artery disease (CAD). METHODS AND RESULTS: One hundred and two female patients (57±10 years) who underwent DSE as part of the Korean women's chest pain registry study were included. Doppler echocardiography was performed during DSE to assess the presence of DLVOTO. Patients with DLVOTO (n=52) were older than those without DLVOTO (n=50; P=0.001). Hypertension was more prevalent in patients with DLVOTO (P=0.02). Patients with DLVOTO had smaller LV diameter, but higher LV mass index and relative wall thickness (P<0.05 for all). LV diastolic function (as reflected by late diastolic velocity, deceleration time of early diastolic velocity [E], and ratio of E velocity to early diastolic mitral annular velocity), was worse in patients with DLVOTO (P<0.05 for all). Patients with DLVOTO had shorter exercise time (P=0.02) and lower amount of work (P=0.04) than patients without DLVOTO. DSE-provoked DLVOTO was not related to the presence of CAD in these patients. CONCLUSIONS: In Korean women with suspected CAD, DSE-provoked DLVOTO is correlated with LV concentric remodeling and LV diastolic dysfunction, and may be associated with limited exercise tolerance and symptoms of chest pain.

Improvement of Predictive Value for Thromboembolic Risk by Incorporating Left Atrial Functional Parameters in the CHADS2 and CHA2DS2-VASc Scores.

The discriminative ability of the widely used CHADS2 and CHA2DS2-VASc scores for risk stratification of thromboembolism in atrial fibrillation (AF) is known as modest. Some echocardiographic parameters are known risk factors for thromboembolism. This study aimed to evaluate whether combining echocardiographic parameters with CHADS2 and CHA2DS2-VASc scores can improve the predictive power for embolic risk in AF.A total of 526 (F/M = 83/433, mean age = 57.6 ± 10.7 years) patients with non-valvular AF were enrolled. The predictability for left atrial (LA) thrombus or dense spontaneous echo contrast (SEC) using clinical scores or echocardiographic parameters or combining clinical scores and echocardiographic parameters was calculated and compared.Dense SEC or thrombus was present in 51 patients. The predicting powers of the CHADS2 and CHADS2-VASc scores for the presence of dense SEC or thrombus were modest (c-statistics 0.65 and 0.68, respectively, 95% confidence interval [CI] 0.61-0.69 and 0.64-0.74, respectively, both P < 0.001). Impaired LA function was the most descriptive predictor for the presence of thrombus or dense SEC among echocardiographic parameters. Combining impaired LA function (LA emptying fraction < 30%) with the CHADS2 and CHA2DS2-VASc scores showed the improvement of predictive power in detecting dense SEC or thrombus (c-statistics 0.78 and 95% CI 0.74-0.81 and c-statistics 0.77 and 95% CI 0.73-0.81, respectively, both P < 0.001).Adding LA functional markers to the CHADS2 or CHA2DS2-VASc score improved the predictive value of the presence of thrombus or dense SEC. In clinical situations, anticoagulation should be considered to prevent embolism in patients with low-risk scores when they have LA dysfunction.

Should preoperative chest CT be recommended to all colon cancer patients?

OBJECTIVE: The aim of this study was to evaluate the efficacy of preoperative chest computed tomography (CT) and the risk factors for lung metastasis in colon cancer patients without liver metastasis who had negative findings on initial chest X-ray (CXR). BACKGROUND: Preoperative staging with chest CT is recommended in colon cancer patients. However, there have been only scant data on the clinical efficacy. METHODS: Three hundred nineteen consecutive colon cancer patients without liver metastasis were retrospectively reviewed and analyzed. The patients had negative findings on preoperative CXR, and they underwent surgery for colon cancer during the period of January 2008 to April 2010. RESULTS: Lung nodule on chest CT was found in 136 patients (42.6%). Twenty of those were definitely diagnosed with lung metastasis (6.3%) by follow-up chest CT or pathologic confirmation. There was no case of delay in surgery due to findings of lung nodule. Comparing the group with lung metastases to that without lung metastases, postoperative pathologic findings reported more advanced T and N status (P = 0.004, P < 0.001, respectively), and lymphatic invasion was more frequent (P = 0.003) in the group with lung metastasis. By multivariate analysis, CT-predicted lymph node metastases and pathologic lymph node metastases were risk factors for lung metastases. CONCLUSIONS: Preoperative staging chest CT is not beneficial to colon cancer patients without liver metastasis and lymph node metastasis suggested on abdominal and pelvic CT who had negative finding on initial CXR.

Effects of dietary salt restriction on renal progression and interstitial fibrosis in adriamycin nephrosis.

BACKGROUND/AIMS: Although high salt intake is thought to accelerate renal progression in proteinuric kidney disease, it is not known whether strict dietary salt restriction could delay renal inflammation and interstitial fibrosis. Here, we sought to answer this question in a rat model of adriamycin-induced nephrotic syndrome. METHODS: Adriamycin was administered via the femoral vein in a single bolus (7.5 mg/kg), and the rats were put on a sodium-deficient rodent diet. Rats with intact kidneys were studied for 5 weeks (experiment 1), and uninephrectomized rats were studied for 6 weeks (experiment 2). RESULTS: In experiment 1, restricting salt intake improved renal tubulointerstitial histopathology in adriamycin-treated rats. Immunohistochemical and immunoblot results additionally showed that restricting dietary salt lowered adriamycin-induced expression of osteopontin, collagen III, and fibronectin. In experiment 2, salt restriction improved adriamycin-induced azotemia, although it did not affect proteinuria or blood pressure. Dietary salt restriction also reduced adriamycin-induced infiltration of ED1-positive cells and the upregulated expression of osteopontin and α-SMA. Masson's trichrome and Sirius red staining revealed that salt restriction slowed Adriamycin-induced progression of renal interstitial fibrosis. Finally, qPCR revealed that adriamycin-induced expression of TNF-α, IκB-α, gp91(phox), p47(phox), and p67(phox) mRNA was blocked by salt restriction. CONCLUSION: Our findings demonstrate that strict dietary salt restriction delays the progress of renal inflammation and fibrosis in proteinuric kidney disease, most likely via relieving the reactive oxygen species-mediated NF-κB activation.

Presence of preoperative diastolic dysfunction predicts postoperative pulmonary edema and cardiovascular complications in patients undergoing noncardiac surgery.

OBJECTIVE: The aim of this study was to evaluate the impact of left ventricular diastolic dysfunction on predicting postoperative pulmonary edema and major cardiovascular events (MACE) in patients who underwent low- or intermediate-risk noncardiac surgery. METHODS: A total of 692 patients aged >60 years who underwent transthoracic echocardiography (TTE) before undergoing elective low- or intermediate-risk noncardiac surgery were prospectively enrolled. The medical history and TTE variables were assessed. Each patient was clinically evaluated for postoperative pulmonary edema and MACE. The presence of postoperative pulmonary edema and MACE were evaluated during a 30-day follow-up period after surgery. RESULTS: We identified 166 patients with pulmonary edema and 49 patients with MACE. After adjusting for clinical and TTE variables, multivariate analysis demonstrated that a ratio of early transmitral flow velocity to early diastolic velocity of the mitral annulus (E/e') >15, pulmonary artery systolic pressure (PASP) ≥35 mmHg, and left ventricular hypertrophy (LVH) were significantly associated with postoperative pulmonary edema (E/e', P < 0.001: PASP, P = 0.005; LVH, P = 0.017). The multivariate analysis for MACE after adjusting for clinical risk factors indicated that MACE were significantly associated with an E/e' > 15 (P < 0.001). CONCLUSION: E/e' > 15, PASP elevation, and LVH on preoperative TTE predicted postoperative pulmonary edema, and E/e' > 15 predicted MACE in the patients who underwent low- or intermediate-risk noncardiac surgery. Thus, we believe that clinicians need to be cautious when providing perioperative care to patients with high E/e' ratios who are indicated for TTE.

The difference of predictors for recurrence after catheter ablation of non-paroxysmal atrial fibrillation according to follow-up period.

The aim of this study was to assess the clinical and echocardiographic predictors for the recurrence of persistent atrial fibrillation (AF) after ablation during a long-term period.A total of 130 patients with persistent AF who had undergone radiofrequency catheter ablation (RFCA) were enrolled. We analyzed the relation between clinical parameters, echocardiographic parameters, and AF recurrences at 6 months, 1 year, and 2 years after ablation.During the 2-year follow-up, AF recurred in 61 patients (46.6%). In the 6 month follow-up, AF recurrence was associated only with total ablation time only. However, during the 1-year and 2-year follow-up periods, the presence of hypertension, impaired left atrial (LA) emptying fraction (eF) (≤ 20%), decreased LA appendage (LAA) emptying velocity (≤ 20 cm/sec), and LAAeF (≤ 20%) were correlated with AF recurrence (odds ratio [OR] = 1.87, 2.45, 1.93, and 2.15 respectively, P = 0.016, 0.004, 0.029, and 0.004 respectively). Among these factors, impaired LAeF was the only independent predictor of AF recurrence in multivariate analysis (OR = 2.81, P = 0.012).In patients with persistent AF who had undergone RFCA, the best predictor of AF recurrence after ablation varied according to the follow-up period. Diminished LA function was the only predictor of recurrence in the 2-year follow-up. Pre-procedural assessment of LA function might be helpful in selecting those patients who would benefit from RFCA.

Acute and chronic effects of dietary sodium restriction on renal tubulointerstitial fibrosis in cisplatin-treated rats.

BACKGROUND: Renal interstitial fibrosis is a major complication of cisplatin (CP) treatment, and increased sodium intake may accelerate its progression by stimulating transforming growth factor (TGF)-ß/Smad signaling. However, it is not clear whether a low-sodium diet has beneficial effects on the development of interstitial fibrosis because it activates the renin-angiotensin-aldosterone system. Here, we tested whether the TGF-ß/Smad signaling pathway is stimulated in CP-treated rats, and whether the development of tubulointerstitial fibrosis in CP nephropathy can be checked by dietary sodium restriction. METHODS: Male Sprague Dawley rats were randomly divided into controls, CP treatment and CP treatment with low-sodium diet. The acute experiment lasted 7 days with a single intraperitoneal injection (6 mg/kg) of CP, and the chronic experiment involved weekly injections (2 mg/kg) for 7 weeks. RESULTS: In both sets of experiments, CP treatment produced pronounced tubulointerstitial injury, increased infiltration of ED1-positive cells and increased expression of monocyte chemotactic protein-1 (MCP-1), α-smooth muscle actin (SMA), TGF-ß1, phosphorylated Smad3, fibronectin and collagen III proteins. In the acute experiment, the increases in expression of osteopontin, MCP-1, α-SMA, TGF-ß and collagen III were significantly reduced by dietary sodium restriction. In the chronic experiment, however, none of the measurements were improved by a low-sodium diet. Examination of CP-treated rat kidneys revealed de novo vimentin expression in tubular epithelial cells and invasion of α-SMA-positive tubular epithelial cells through the basement membrane into the interstitium. CONCLUSIONS: The pro-fibrotic effect of TGF-ß in CP nephropathy appears to be associated with the epithelial-mesenchymal transition and is ameliorated by dietary sodium restriction only during the acute phase.

Effect of mycophenolic acid on cyclosporin A-induced fibronectin expression in rat mesangial cells.

This study was undertaken to determine if mycophenolic acid (MPA) inhibits the profibrotic action of cyclosporin A (CsA) and, if so, to determine the molecular mechanisms involved. The effect of MPA treatment on CsA-induced signaling through the transforming growth factor-ß (TGF-ß)/Smad pathway was evaluated by immunoblot analysis in cultured primary rat mesangial cells. Treatment of cells with 1 µmol/l MPA did not significantly decrease the CsA-induced expression of TGF-ß(1), but partially reversed the increases in Smad3 phosphorylation and fibronectin (FBN) production, and increased Smad7 expression. These results suggest that MPA may ameliorate CsA-induced FBN production by modulating the Smad signaling pathway. This study provides evidence that MPA can attenuate CsA-induced renal injury after kidney transplantation.

Effects of sitagliptin on peritoneal membrane: The potential role of mesothelial cell tight junction proteins.

BACKGROUND: The roles of tight junction (TJ) proteins in peritoneal membrane transport and peritoneal dialysis (PD) require further characterisation. Dipeptidyl peptidase-4 is expressed in mesothelial cells, and its activity may affect peritoneal membrane function and morphology. METHODS: Human peritoneal mesothelial cells (HPMCs) were isolated and cultured from omentum obtained during abdominal surgery, and paracellular transport functions were evaluated by measuring transmesothelial electrical resistance (TMER) and dextran flux. Sprague-Dawley rats were infused daily with 4.25% peritoneal dialysate with and without sitagliptin administration for 8 weeks. At the end of this period, rat peritoneal mesothelial cells (RPMCs) were isolated to evaluate TJ protein expression. RESULTS: In HPMCs, the protein expression of claudin-1, claudin-15, occludin and E-cadherin was decreased by TGF-ß treatment but reversed by sitagliptin co-treatment. TMER was decreased by TGF-ß treatment but improved by sitagliptin co-treatment. Consistent with this, dextran flux was increased by TGF-ß treatment and reversed by sitagliptin co-treatment. In the animal experiment, sitagliptin-treated rats had a lower D2/D0 glucose ratio and a higher D2/P2 creatinine ratio than PD controls during the peritoneal equilibration test. Protein expression of claudin-1, claudin-15 and E-cadherin decreased in RPMCs from PD controls but was not affected in those from sitagliptin-treated rats. Peritoneal fibrosis was induced in PD controls but ameliorated in sitagliptin-treated rats. CONCLUSION: The expression of TJ proteins including claudin-1 and claudin-15 was associated with transport function both in HPMCs and in a rat model of PD. Sitagliptin prevents peritoneal fibrosis in PD and can potentially restore peritoneal mesothelial cell TJ proteins.