Elevated Soluble Podoplanin Associates with Hypercoagulability in Patients with Nephrotic Syndrome.

Podoplanin (PDPN) promotes platelet aggregation and activation by interacting with C-type lectin-like receptor 2(CLEC-2) on platelets. The interaction between the upregulated PDPN and platelet CLEC-2 stimulates venous thrombosis. PDPN was identified as a risk factor for coagulation and thrombosis in inflammatory processes. Hypercoagulability is defined as the tendency to develop thrombosis according to fibrinogen and/or D dimer levels. Nephrotic syndrome is also considered to be a hypercoagulable state. The aim of this study is to investigate the association of soluble PDPN/CLEC-2 with hypercoagulability in nephrotic syndrome. Thirty-five patients with nephrotic syndrome and twenty-seven healthy volunteers were enrolled. PDPN, CLEC-2 and GPVI concentrations were tested by enzyme-linked immunosorbent assay (ELISA). Patients with nephrotic syndrome showed higher serum levels of PDPN and GPVI in comparison to healthy controls (P < .001, P = .001). PDPN levels in patients with nephrotic syndrome were significantly correlated with GPVI (r = 0.311; P = .025), hypoalbuminemia (r = -0.735; P < .001), hypercholesterolemia (r = 0.665; P < .001), hypertriglyceridemia (r = 0.618; P < .001), fibrinogen (r = 0.606; P < .001) and D-dimer (r = 0.524; P < .001). Area under the curve (AUC) for the prediction of hypercoagulability in nephrotic syndrome using PDPN was 0.886 (95% CI 0.804-0.967, P < .001). Cut-off value for the risk probability was 5.88 ng/ml. The sensitivity of PDPN in predicting hypercoagulability was 0.806, and the specificity was 0.846. When serum PDPN was >5.88 ng/ml, the risk of hypercoagulability was significantly increased in nephrotic syndrome (OR = 22.79, 95% CI 5.92-87.69, P < .001). In conclusion, soluble PDPN levels were correlated with hypercoagulability in nephrotic syndrome. PDPN has the better predictive value of hypercoagulability in nephrotic syndrome as well as was a reliable indicator of hypercoagulable state.

Assessment of Renal Function and Risk Factors for Chronic Kidney Disease in Patients With Peripheral Arterial Disease.

Chronic kidney disease (CKD) and peripheral arterial disease (PAD) share common risk factors. We assessed renal function and the prevalence of CKD in patients with PAD and investigated the characteristics of the risk factors for CKD in this population. Renal function of 421 patients with PAD was evaluated. Among the participants, 194 (46.1%) patients had decreased estimated glomerular filtration rate (eGFR). The prevalence of CKD was much higher among patients with PAD. Hypertension (odds ratios [ORs] 2.156, 95% confidence interval [CI] 1.413-3.289, P < .001), serum uric acid (OR 3.794, 95% CI 2.220-6.450, P < .001), and dyslipidemia (OR 1.755, 95% CI 1.123-2.745, P = .014) were significantly associated with CKD and the independent risk factors for CKD in patients with PAD. CKD is common and has a high prevalence in a population with PAD. Patients with PAD may be considered as a high-risk population for CKD. Recognition and modification of risk factors for CKD might beneficially decrease CKD incidence and improve prognosis in patients with PAD.

Effect of the oral iron chelator deferiprone in diabetic nephropathy rats.

BACKGROUND: The aim of the present study was to investigate the effects of the iron chelator deferiprone in diabetic nephropathy (DN) rats and the mechanisms involved. METHODS: Thirty-two male Wistar rats (180-220 g, 6 weeks old) were randomly divided into a control group, a DN group and two DN groups treated with either 50 or 100 mg/kg per day deferiprone. The DN group was established by feeding of a high-carbohydrate-fat diet and injection of 35 mg/kg streptozotocin into the vena caudalis. The duration of deferiprone treatment was 20 weeks. Histopathological changes were detected by hematoxylin-eosin and Masson staining, as well as transmission electron microscopy. Levels of nuclear factor (NF)-κB, monocyte chemotactic protein (MCP)-1, matrix metalloproteinase (MMP)-9, tissue-specific inhibitor of metalloproteinase (TIMP)-1, cyclo-oxygenase (COX)-2, and nitrotyrosine were determined in kidney tissues using reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. RESULTS: Histopathological observations showed that deferiprone treatment alleviated inflammation infiltrates and collagenous fibrosis in DN rats. Results from RT-PCR and western blotting indicated that deferiprone inhibited the expression of NF-κB, MCP-1, COX-2, and nitrotyrosine, which were overexpressed in DN rats. Immunohistochemistry showed that the mechanism of deferiprone action may involve regulation of MMP-9 and TIMP-1. Decreased MMP-9 expression and increased TIMP-1 expression in DN rats were significantly promoted and inhibited by deferiprone, respectively. CONCLUSION: Iron chelation by oral deferiprone has a renoprotective effect in DN rats by relieving oxidative stress, inflammation, and fibrosis, which is related to the cytokines NF-κB, MCP-1, MMP-9, TIMP-1, COX-2, and nitrotyrosine.

Original Research: Atorvastatin prevents rat cardiomyocyte hypertrophy induced by parathyroid hormone 1-34 associated with the Ras-ERK signaling.

We investigated the effects of atorvastatin (Ator) on cardiomyocyte hypertrophy (CMH) induced by rat parathyroid hormone 1-34 (PTH1-34) and Ras-extracellular signal regulated protein kinases 1/2 (ERK1/2) signaling. Rat cardiomyocytes were randomly divided into seven groups: normal controls (NC), PTH1-34 (10(-7) mol/L), Ator (10(-5) mol/L), farnesyl transferase inhibitors-276 (FTI-276, 4 × 10(-5) mol/L), PTH1-34 + Ator, PTH1-34 + FTI-276 and PTH1-34 + Ator + mevalonic acid (MVA, 10(-4) mol/L). After treatment, the hypertrophic responses of cardiomyocytes were assessed by measuring cell diameter, detecting protein synthesis, and single-cell protein content. The concentrations of hypertrophic markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured by ELISA. Protein expressions of ERK1/2, p-ERK1/2 and Ras were detected by western blotting. The results showed that compared with the PTH1-34 group, cellular diameter, 3H-leucine incorporation, single-cell protein content, ANP and BNP concentration decreased by 12.07 µm, 1622 cpm/well, 84.34 pg, 7.13 ng/L and 20.04 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were downregulated in PTH1-34 + Ator group (P < 0.05). Compared to the PTH1-34 + Ator group, the corresponding hypertrophic responses and hypertrophic markers increased by 4.95 µm, 750 cpm/well, 49.08 pg, 3.12 ng/L and 9.35 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were upregulated in the PTH1-34 + Ator + MVA group (P < 0.05). In conclusion, Ator prevents neonatal rat CMH induced by PTH1-34 and Ras-ERK signaling may be involved in this process.

Relationship between hypoalbuminemia, hyperlipidemia and renal severity in patients with lupus nephritis: a prospective study.

AIM OF THE STUDY: The purpose is to evaluate the relationship between hypoalbuminemia, hyperlipidemia, nephrotic and renal severity in patients with lupus nephritis. MATERIAL AND METHODS: Autoantibodies and serological parameters were measured and analyzed in 429 patients with lupus nephritis in a single centre. RESULTS: The prevalence for anti-dsDNA, anti-nucleosome and anti-histone was higher in the nephrotic syndrome (NS) patients than that in non-NS patients (p < 0.0001 for all comparisons). The NS patients had a higher proportion of diffuse proliferative renal lesions (69.05%) and membranous lesions (68.00%). Serum total cholesterol and albumin levels were associated with activity and severity of renal disease. The levels of proteinuria and serum albumin were positively correlated with activity and chronicity index (p < 0.001 for all correlations). The incidence of a poor renal outcome (p = 0.0461) in the NS patients was significantly increased. On the other hand, the remission rate (p = 0.0002) was significantly reduced and recurrence rate (p = 0.0027) was significantly increased in NS patients. CONCLUSIONS: This paper highlights that nephrotic-range proteinuria, elevated total cholesterol level and decreased serum albumin levels may reflect the activity and severity of renal damage in SLE patients.

Prevalence and risk factors for chronic kidney disease in patients with coronary artery disease.

OBJECTIVES: Chronic renal disease (CKD) is recognized as a worldwide public health problem. Traditional risk factors for CKD are also present in coronary artery disease (CAD). The purpose of this study is to examine the prevalence and characteristics of risk factors for CKD in the population with CAD. METHODS: Renal function was evaluated in 527 patients with CAD in order to assess characteristics of the incidence, risk factors for CKD in the population with CAD. In the present study in order to concentrate on evaluation for eGFR of the patients with CAD proteinuria is not included in the definition of CKD. RESULTS: Univariate analysis demonstrated that the major risk factors associated with CKD in the patients with CAD were age (P ≤ 0.001), smoking (P = 0.016), diabetes mellitus (P = 0.021), hypertension (P ≤ 0.001), and systolic blood pressure (P = 0.004). The percentages of patients with both hypertension and diabetes mellitus were significantly greater in the CKD3-4 group (P < 0.001). The results of multivariable analysis showed that hypertension (OR 1.925, 95% CI 1.196-3.098, P = 0.007), diabetes mellitus (OR 1.744, 95% CI 1.044-2.914, P = 0.034) and serum uric acid (OR 1.008, 95% CI 1.006-1.010, P ≤ 0.001) were independent risk factors for reduced eGFR. CONCLUSIONS: CKD is common and has a high prevalence in the population with CAD. Several risk factors are known to simultaneously affect heart and kidney. The patients with CAD may be considered as a high-risk population for CKD.

[Atorvastatin attenuates parathyroid hormone 1-34 induced cardiomyocytes hypertrophy through downregulating K-Ras-ERK1/2 pathway].

OBJECTIVE: To investigate the effects of atorvastatin on parathyroid hormone 1-34 (PTH1-34) induced neonatal rat cardiomyocytes hypertrophy and on the expression changes of small GTP-binding protein (K-Ras) and extracellular signal regulated protein kinases 1/2 (ERK1/2). METHODS: Neonatal rat cardiomyocytes hypertrophy was established with 10(-7) mol/L rPTH1-34 in the presence or absence of 10(-5) mol/L atorvastatin or 10(-4) mol/L mevalonic acid (MVA). Cardiomyocyte diameter was measured by Motic Images Advanced 3.0 software, the synthetic rate of protein in cardiomyocytes was determined by (3)H-leucine incorporation and single-cell protein content was measured by BCA. The concentration of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were determined by ELISA. Protein expression of ERK1/2, p-ERK1/2 and K-Ras was detected by Western blot. RESULTS: Compared to PTH1-34 group, cellular diameter was decreased 12.07 µm, (3)H-leucine incorporation decreased 1622 cpm/well and single-cell protein content decreased 84.34 pg, ANP or BNP concentration reduced 7.13 µg/L or 20.04 µg/L, protein expression of K-Ras, ERK1/2 or p-ERK1/2 downregulated 0.81, 0.19 and 1.44 fold, respectively, in PTH1-34 plus atrovastatin co-treated cardiomyocytes (all P < 0.05). Compared to PTH1-34 plus atrovastatin co-treated group, cardiomyocyte diameter increased 4.95 µm, (3)H-leucine incorporation increased 750 cpm/well and single-cell protein content increased 49.08 pg, ANP or BNP increased 3.12 µg/L or 9.35 µg/L and protein expression of K-Ras, ERK1/2 or p-ERK1/2 upregulated 0.52, 0.06 and 1.19 fold (all P < 0.05) in MVA, PTH1-34 and atrovastatin co-treated cardiomyocytes. CONCLUSIONS: Atrovastatin attenuates PTH1-34 induced neonatal rat cardiomyocytes hypertrophy through downregulating K-Ras and ERK1/2 pathway.

The sphingosine-1-phosphate receptor agonist FTY720 prevents the development of anti-glomerular basement membrane glomerulonephritis.

The sphingosine-1-phosphate (S1P) agonist FTY720 prolongs the survival of organ allograft and attenuates autoimmune-mediated injury in experimental models. Most cases of glomerulonephritis (GN) in human appear to be immunologically initiated. In this study, we evaluated the potential therapeutic role of FTY720 in GN via a mouse anti-glomerular basement membrane (GBM) model. Mice were immunized with rabbit IgG in complete Freund's adjuvant (CFA) followed by an intravenous injection of a rabbit anti-mouse GBM serum. Disease and immune responses were assessed on day 14. Mice were treated with FTY720 (0.3 or 3 mg/kg) and prednisone (10 mg/kg) from days 0 to 14. The S1P modulator reduced proteinuria, serum creatinine, crescent formation and serum IgG level. The expressions of splenic S1P receptor and renal Th-1 cytokine were also inhibited at the transcription stage. Treatment with FTY720 increased splenocyte production of protective Th2 cytokine IL-4 and promoted the apoptosis of splenic CD4+ T cells in the animal models, which suggests that FTY720 played a protective role at the induction stage of GN by inhibiting mRNA expressions of splenic S1P receptor 1, S1P receptor 2, and S1P receptor 5.

Characterization of interleukin-33 and soluble ST2 in serum and their association with disease severity in patients with chronic kidney disease.

INTRODUCTION: This study aims to test the serum levels of interleukin-33 (IL-33) and soluble ST2 (sST2) in patients with chronic kidney disease (CKD) and to evaluate their association with disease severity. METHODS: Sixty-nine patients with CKD were enrolled, disease severity was assessed, and clinical data were collected. Twelve healthy volunteers served as healthy individuals. Serum IL-33 and sST2 were tested by enzyme-linked immunosorbent assay. RESULTS: The patients were classified into five categories based on their estimated glomerular filtration rate (eGFR). No difference was found as to the serum concentration of IL-33 between CKD patients and healthy individuals (p = 0.656), while a higher serum level of sST2 was found in CKD patients (p = 0.003). The correlation analysis revealed a significant correlation between the serum level of sST2 and disease severity (r = 0.586; p < 0.001). A higher level of sST2 was found in CKD patients with elevated parathyroid hormone (p = 0.001). Serum sST2 correlated with parathyroid hormone (r = 0.412; p < 0.001), serum phosphorus (r = 0.545; p < 0.001), and serum calcium (r = -0.494; p < 0.001). CONCLUSION: An elevated concentration of serum sST2 is found in CKD patients and correlates with disease severity. Serum sST2 may be also associated with parathyroid hormone disorder of CKD. The sST2 may have an important role in the development of CKD or as a marker of disease severity.

N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal inflammation and tubulointerstitial fibrosis in rats.

It has been reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) attenuates renal and cardiac inflammation as well as fibrosis in hypertensive rats. In this study, we investigated these effects using a unilateral ureteral obstruction (UUO) model. Eighteen male Wistar rats were randomly divided into three groups: control, UUO/vehicle and UUO/Ac-SDKP groups. Animal models of renal inflammation and tubulointerstitial fibrosis were established with unilateral ureteral ligation in rats. Ac-SDKP and vehicle were infused subcutaneously by using osmotic mini pumps for two weeks. On the 14th day post-injection, kidney histological changes of each group were observed by hematoxylin-eosin and Masson's stain. Renal macrophage infiltration, together with protein expression and localization of monocyte chemoattractant protein-1 (MCP-1), nuclear factor-kappa B (NF-κB), α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1) in renal tissue was assessed by immunohistochemical staining. Gene expression of MCP-1 and TGF-ß1 was analyzed with reverse transcription-polymerase chain reaction. Ac-SDKP-treated animals demonstrated less severe renal inflammation and tubulointerstitial fibrosis. Interstitial fibrosis was significantly attenuated with Ac-SDKP. ED-1 was expressed in the interstitium of the UUO/vehicle group kidneys and decreased with Ac-SDKP treatment. MCP-1, NF-κB, α-SMA and TGF-ß1 were increased in the renal interstitium and tubular epithelial cells of the UUO/vehicle group. Ac-SDKP significantly reduced their expressions. Gene expressions of MCP-1 and TGF-ß1 were upregulated in the UUO/vehicle group kidneys and were significantly inhibited by Ac-SDKP. In conclusion, in the rat UUO model Ac-SDKP administration protected against renal inflammation and tubulointerstitial fibrosis. The inhibitory effect of Ac-SDKP was mediated by the reduction in the expression of MCP-1, NF-κB, α-SMA and TGF-ß1.

[Expression and significance of CD80/CD86 in renal tissue of lupus nephritis].

OBJECTIVE: To measure the expression of CD80 and CD86 in renal tissue of lupus nephritis (LN) and explore its mechanism in the development of LN. METHODS: Forty-nine patients with active LN and 9 patients with minor glomerular abnormalities tissues as controls were studied. The expression of CD80 and CD86 in renal tissues was detected by immunohistochemical methods. RESULTS: CD86 was expressed extensively in glomerulus, periglomerular area, tubular epithelial cells and peritubular interstitium, while CD80 was expressed only in tubular epithelial cells and peritubular interstitium. Moreover, the percentage of CD80+ and CD86+ cells in tubular epithelial cells and peritubular interstitium showed a tendency to increase with tubulointerstitial damage. The expression of CD80 and CD86 in renal tissue correlated with the systemic lupus erythematosus (SLE) disease activity index score, the degree of proteinuria, creatinine clearance and anti-dsDNA antibody. CONCLUSIONS: This study shows that increased CD80 and CD86 expression with the progression of tubulointerstitial lesion might play an important role in the development of lupus nephropathy, and the tubulointerstitial expression of CD80 and CD86 could potentially serve as a surrogate marker of SLE disease activity. The co-stimulatory molecules CD80 and CD86 might play an important role in the pathogenesis of LN.