Decrease In Cystatin Research Articles

Differential Renoprotective Actions of Simvastatin and Rosuvastatin in Streptozotocin-Induced Diabetes in Sprague-Dawley Rat

Diabetic nephropathy (DN) is the most frequent cause of the end-stage renal disease (ESRD) in about 33% of diabetic patients. The present study aimed to explore the renoprotective effects of simvastatin (SV) and rosuvastatin (RSU) on the kidney of streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rat model. As a result of induction of diabetes, serum [cystatin C, transforming growth factor-beta (TGF-β), and 8-hydroxy-2' -deoxyguanosine (8-OHdG)] and tissue [interleukin 1 beta (IL-1β), interleukin 10 (IL-10), prostaglandin E2 (PGE2), cytochrome c, malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), GSH/GSSG ratio) markers showed significant increase than negative controls except tissue total glutathione (tGSH). Both SV and RSU significantly shifted the levels back toward near non-diabetic values. Both exerted the same renoprotective effect indicated by a significant decrease in cystatin C. However, SV significantly lowered IL-10, GSH/GSSG ratio, MDA, and 8-OHdG than RSU. Similarly, RSU significantly lowered cytochrome c and GSSG than SV. In conclusion, SV and RSU have differential renoprotective effects via alteration of growth factor, inflammatory, oxidative stress, DNA damage, and apoptotic signaling pathways.

P0193MEASUREMENTS OF SERUM CREATININE AND EGFR IN PATIENTS WITH CHRONIC CARDIORENAL SYNDROME TYPE 2 ARE INSUFFICIENT TO ASSESS RENAL RESPONSES TO RESYNCHRONIZATION THERAPY DURING A TREE-MONTH FOLLOW-UP

Abstract Background and Aims Chronic cardiorenal sydrome type 2 (CRS-T2) has a complex pathophysiology. Treatment and evaluation of the clinical effects of CRS-T2 therapy is difficult in clinical practice. The study’s aim was to non-invasively assess renal function using biomarkers associated with nephron injury sites in patients with CRS-T2 following cardiac resynchronization therapy (CRT). Method The study included patients with CRS-T2 and heart failure in NYHA classes II-IV, in whom CRT devices had been implanted. Before cardiac resynchronization therapy and after 3 months, patients’ renal function was assessed using biomarkers measured in single urine and blood samples. Test results were correlated with cardiovascular fitness assessments. Results CRT was implanted in 56 (n = 17; 30.4% ♀) patients with a mean age of 66 ± 10 years with CRS-T2 in the course of coronary artery disease (n = 38) or dilated cardiomyopathy (n = 18) with eGFRCKD-EPI = 68.55 ± 20.34 ml / min / 1.73m2. The three-month follow-up was continued in 33 (61.11%) patients. Three months after implantation CRT, the responders group cardiovascular endurance improved by at least on NYHA class; showed a significant decrease in NT-pro BNP (n = 24; 72.72%; p = 0.004), a significant (p < 0.05) decrease in serum prostaglandin D2 synthase (sPGD2S) and albuminuria (uACR) concentrations (Figure 1 a), and increases in hematocrit (HCT), erythrocyte count (RBC) and hemoglobin (Hb). The urine samples of the non-responders group following CRT, showed significant (p <0.05) increases in lipocalin concentrations associated with neutrophil gelatinase (uNGAL), and a decrease in cystatin C (uCysC) concentrations (Figure 1 b). There were no significant changes in the concentration of serum creatinine (sCr), eGFRCKD-EPI, serum cystatin C or uromodulin in urine and serum; and urinary kidney injury molecule-1 (uKIM-1) was found in the urine of both responding and nonresponding groups (p> 0.05). Conclusion The sCR and eGFR CKD-EPI assessment should not be used to assess renal function in patients with type 2 chronic cardiac renal syndrome who have undergone CRT implantation. Renal function biomarkers that account for the pathophysiology of nephron injury and correlated with myocardial function: sPGD2S, uACR, uCysC, uNGAL. Also, increased HCT, RBC, and Hb are characteristic in responders.

Serum cystatin C levels are decreased in type 1 diabetes mellitus patients with diabetic ketoacidosis.

Cystatin C is a marker of renal function and risk factor for cardiovascular disease. Patients with acute myocardial infarction showed a significant decrease in cystatin C levels. It is unknown whether reduced serum cystatin C levels are connected to acute events or represent a negative acute phase response. The current study aimed to assess the association between cystatin C and the existence of diabetic ketoacidosis (DKA), an acute event in individuals with type 1 diabetes mellitus (T1DM). Cystatin C was measured in the control group (N.=322) and in T1DM patients with (N.=161) and without DKA (N.=146). Data were compared according to diabetes and ketoacidosis status. Correlation analysis was used to identify factors associated with cystatin C levels. A multiple stepwise regression analysis was used to determine which of the parameters that were significantly correlated with cystatin C in univariate analysis were independently related to cystatin C. Then, we assessed the independent association between cystatin C and the occurrence of DKA in T1DM patients. Serum cystatin C levels were lower in patients with DKA than in patients without DKA. After adjustment for age, sex, fasting plasma glucose and creatinine, cystatin C was positively correlated with the duration of diabetes, systolic blood pressure (SBP), total cholesterol, triglycerides, uric acid and low-density lipoprotein cholesterol (P=0.004, P=0.022, P=0.013, P=0.035, P=0.006, P=0.012, respectively) and negatively correlated with hemoglobin (P<0.001). The duration of diabetes (P<0.001), total cholesterol (P=0.002), hemoglobin (P<0.001), SBP (P=0.011) and serum creatinine (P<0.001) were independently associated with cystatin C. Furthermore, we found that cystatin C was independently associated with the occurrence of DKA in T1DM patients (OR=0.004, 95% CI: 0.000-0.079, P<0.001). Cystatin C was decreased in T1DM patients with DKA and was found to be an independent predictor of the occurrence of DKA in T1DM patients. The reduction in cystatin C levels might be significantly connected with acute events.

Comparative analysis of proteomes between diabetic and normal human sperm: Insights into the effects of diabetes on male reproduction based on the regulation of mitochondria-related proteins.

This study sought to identify sources of the reduced fertility of men with type 2 diabetes mellitus. Significant reductions in semen volume, sperm concentration, and total sperm count were observed in diabetic individuals, while transmission electron microscopy revealed that the structure of mitochondria in the tail of sperm from diabetic patients was damaged. Proteins potentially associated with these sperm defects were identified using proteomics. Isobaric tagging for relative and absolute quantitation labeling and high-performance liquid chromatography-tandem mass spectrometry allowed us to identify 357 proteins significantly differentially expressed in diabetic versus control semen (>1.2 or <0.83). According to gene ontology enrichment and pathway analyses, many of these differentially expressed proteins are associated with sperm function, including binding of sperm to the zona pellucida and proteasome function; of particular interest, half of these proteins were related to mitochondrial metabolism. Protein-interaction networks revealed that a decrease in Cystatin C and Dipeptidyl peptidase 4 in the mitochondria may be sources of the decreased motility of sperm from diabetic patients.

Neither creatinine- nor cystatin C-estimated glomerular filtration rate is optimal in oncology patients treated with targeted agents.

In the last decade, there has been an increase in the use of anti-angiogenic drugs as treatment for metastatic malignancies. However, use of these targeted therapies could induce both glomerular and tubular damage. Also during targeted therapy, the lysosomal protease cathepsin D is released from the tumour, which is inhibited by the protease inhibitor cystatin C. The aim of this study is to determine if use of cystatin C-estimated glomerular filtration rate (eGFR) is applicable to a patient cohort treated with targeted agents. A cohort of 80 patients with various malignancies were continuously recruited and prospectively analysed. Serum and urinary biochemical analytes for renal toxicities were assessed at different time points during treatment. The association between serum cystatin C and cathepsin D was also determined. A decrease in serum cystatin C concentrations (1.03 versus 0.90 mg/L; P < 0.001), together with an increase in cystatin C-eGFR (71 versus 89 mL/min/1.73 m2; P = 0.002) was observed during therapy, compared with baseline. This decrease in cystatin C concentrations was correlated with cathepsin D (r = 0.307; P < 0.001), which was released from the tumour during targeted therapy. Further analysis demonstrated cathepsin D-mediated proteolysis of cystatin C in serum. Cystatin C concentrations were decreased during targeted therapy due to cathepsin D-mediated proteolysis. Cystatin C-eGFR is therefore not considered a suitable marker for assessing kidney function in oncology patients, and other techniques to estimate the GFR have to be applied in this patient population.

Relation of Activity Patterns and Biochemical Factors to Acute Mountain Sickness in the South Pole

Acute Mountain Sickness (AMS) can develop during rapid altitude exposure. It is a subjective diagnosis that commonly consists of symptoms related to headaches, fatigue, sleeplessness and dizziness, while more severe AMS can deteriorate to conditions that can be life threatening. The role of physical activity in the development of AMS remains controversial. Individuals working at the South Pole are required to make a rapid transition to altitude and be moderately active. PURPOSE: To compare activity patterns and biochemical factors in individuals with and without AMS or its symptoms. METHODS: Venous blood samples were taken from 43 healthy individuals at sea level and 2 days after high altitude exposure. Physical activity was monitored using BodyMedia activity monitors. AMS symptoms were examined using modified Louise Questionnaires. Comparisons were made using paired T-test with repeated measures and Pearson’s correlation. RESULTS: 29% of subjects displayed AMS between SP days 1–2 (D1-2). Total increase in energy expenditure on day 2 for AMS individuals was 16.8%±4.1% and 10.1%±4.9% for individuals without AMS. In addition, for patients with a total symptom score greater than 5, the time spent performing moderate and vigorous activity during D1-2 was greater by a factor of 1.77±0.24 to that of the baseline, and compared to patients with a symptom score less than 5 had a lower increase of 1.34± 0.23. Blood samples presented an increase in VEGF (82.7%), increase in EPO (27.4%), decrease in Cystatin C (−5.1%), and decrease in NE (−1.68%) for AMS individuals. A correlation of total symptom score and time of moderate and vigorous activity expenditure of individuals resulted in at R squared value of 0.66. Comparisons were statistically significant with a p value of p<0.05. CONCLUSION: Increases in activity and evaluation of blood chemistry compared to the baseline after 48 hours of ascent are associated to the risk of AMS.

HIV-1–infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase

AbstractDendritic cells (DCs) play a key role in the pathogenesis of HIV infection. HIV interacts with these cells through 2 pathways in 2 temporal phases, initially via endocytosis and then via de novo replication. Here the transcriptional response of human DCs to HIV-1 was studied in these phases and at different stages of the virus replication cycle using purified HIV-1 envelope proteins, and inactivated and viable HIV-1. No differential gene expression was detected in response to envelope. However, more than 100 genes were differentially expressed in response to entry of viable and inactivated HIV-1 in the first phase. A completely different set of genes was differentially expressed in the second phase, predominantly in response to viable HIV-1, including up-regulation of immune regulation genes, whereas genes encoding lysosomal enzymes were down-regulated. Cathepsins B, C, S, and Z RNA and protein decreased, whereas cathepsin L was increased, probably reflecting a concomitant decrease in cystatin C. The net effect was markedly diminished cathepsin activity likely to result in enhanced HIV-1 survival and transfer to contacting T lymphocytes but decreased HIV-1 antigen processing and presentation to these T cells.

Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial

Creatine (CR) supplementation is commonly used by athletes. However, its effects on renal function remain controversial. The aim of this study was to evaluate the effects of creatine supplementation on renal function in healthy sedentary males (18-35 years old) submitted to exercise training. A randomized, double-blind, placebo-controlled trial was performed. Subjects (n = 18) were randomly allocated to receive treatment with either creatine (CR) ( approximately 10 g day(-1) over 3 months) or placebo (PL) (dextrose). All subjects undertook moderate intensity aerobic training, in three 40-min sessions per week, during 3 months. Serum creatinine, serum and urinary sodium and potassium were determined at baseline and at the end of the study. Cystatin C was assessed prior to training (PRE), after 4 (POST 4) and 12 weeks (POST 12). Cystatin C levels (mg L(-1)) (PRE CR: 0.82 +/- 0.09; PL: 0.88 +/- 0.07 vs. POST 12 CR: 0.71 +/- 0.06; PL: 0.75 +/- 0.09, P = 0.0001) were decreased over time, suggesting an increase in glomerular filtration rate. Serum creatinine decreased with training in PL but was unchanged with training in CR. No significant differences were observed within or between groups in other parameters investigated. The decrease in cystatin C indicates that high-dose creatine supplementation over 3 months does not provoke any renal dysfunction in healthy males undergoing aerobic training. In addition, the results suggest that moderate aerobic training per se may improve renal function.

Cystatin C and cathepsins in cardiovascular disease

Cystatin C and cathepsins could play a role in almost all processes involved in atherosclerotic lesion formation by their degradation of extracellular matrix proteins and apolipoprotein B100, the protein moiety of LDL. Several cysteine cathepsins are upregulated in human lesions accompanied by a decrease in cystatin C, the major inhibitor of cysteine cathepsins. Recent research show that atherosclerotic mice deficient in cystatin C display increased elastic lamina degradation as well as larger plaque formation. Cathepsin S- and K-deficient atherosclerotic mice, on the other hand, both have less atherosclerosis, where cathepsin S-/- mice exhibited fewer plaque ruptures and cathepsin K-/- larger foam cells than control mice. This article reviews possible roles of cystatin C and cathepsins in different processes and stages of the atherosclerotic disease.

Seizures, Ataxia, and Neuronal Loss in Cystatin B Heterozygous Mice

Unverricht-Lundborg disease (EPM1) has been considered to be an autosomal-recessive disease related with loss of function mutations in the gene encoding cystatin B. Although heterozygous carriers are generally asymptomatic, earlier studies in Finnish EPM1 families have reported minor symptoms together with slight changes in the EEG recordings also in near relatives of patients. Here we tested the hypothesis that EPM1 phenotype is expressed also in heterozygous subjects using 17-month-old cystatin B deficient mice as a model of disease. Western blot analysis demonstrated a 50% decrease in cystatin B expression in the cerebellum of these animals. Heterozygous mice showed significantly impaired rotarod performance and were weaker in the grid test. Also the total seizure-rating score of heterozygous animals was higher than in wild-type mice. The stereological analysis revealed a significant decrease in the number of neurons in cerebral cortex and the granule cell layer of cerebellum. These results suggest that partial decrease in cystatin B expression in heterozygous mice could lead to the development of mild EPM1 phenotype.

Cystatin C levels in sera of patients with human immunodeficiency virus infection. A new avidin-biotin ELISA assay for its measurement.

A solid-phase enzyme-linked immunosorbent assay (ELISA) for determining human serum cystatin C is described. In 50 normal samples, cystatin C concentration was 1247 +/- 224 micrograms/L (mean +/- SD) which is in agreement with previously reported levels. Serum levels of cystatin C and beta 2-microglobulin (beta 2-M) were investigated in a time-course study during the development of human immunodeficiency virus (HIV) infection. We found a persistent and uniform increase in the beta 2-M concentration (2762 +/- 1239 micrograms/L). In contrast to beta 2-M, on the basis of cystatin C levels, we found two distinct populations, one of which demonstrated an increased concentration (1620 +/- 618 micrograms/L). Interestingly a second group (21% of patients) exhibited an initial significant decrease in cystatin C concentration with a mean value of 377 (range 55-850) micrograms/L, followed by an increase. The biphasic pattern of cystatin C serum, a major cysteine proteinase inhibitor, during the course of HIV infection suggests a possible role for these proteinases (or proteinase inhibitors) in the development of this syndrome.