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Effects of the SSYZ Caspule on the Leptin Recptor Gene Expression and Signal Transmission in Chronic Renal Failure Rats with Malnutrition

Author: LiYuMing
Tutor: WeiLianBo
School: First Military Medical University
Course: Chinese and Western Medicine
Keywords: CRF Malnutrition Shen-shuai-yang-zhen Hypothalamus Ob-Rb Signal transduction
CLC: R285.5
Type: PhD thesis
Year: 2007
Downloads: 235
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Malnutrition is common complications in patients with CRF. And its prevalence both in the no-dialysis period and during dialysis is high. From foreign literatures, ma lnutrition was found up to 70%during maintenance HD patients and recent data from the Europe and North America Renal Data System registry suggest that about 41-%of 224 patients undergoing CAPD in six kidney dialysis center suffer from malnutrition. More than 65%ESRD had varying degrees of malnutrition reported in the domestic literatures. Malnutrition is known to induce a state of immunodeficiency and aggravate anemia, or lead to multiple system organ failure. This is a problem of substantial importance because many measures of nutritional status correlate with the risk of morbidity and mortality. The researches of malnutrition in CRF patients become a key task.The aetiology and pathogenesis of malnutrition in CRF are complex. and may include many factors, e.g. poor food intake because of anorexia, nausea and vomiting due to uraemic toxicity, hormonal isturbances, enhanced protein catabolism, acidiosis and increased resting energy expenditure. More recently, reducing food intake has been pointed to as an important factor in a worsening of the nutritional status. Leptin is a 16 kDa hormonal protein synthesized mainly by adipose tissue. Leptin is a weight homeostasis regulating hormone, that reduces appetite and increases energy expenditure. Recent epidemiologic studies have suggested that increased serum levels of leptin may reduce nutrient intake and contribute to the development of malnutrition. Leptin has long been associated with malnurtion in CRF patients. It is believed that high leptin levels is common in CRF patients. Serum leptin levels are high in CRF patients, mainly because leptin is degraded in the kidney, but serum leptin levels are also closely associated with inflammation, hyperinsulinemia and hypercholesterolaem-ia that can upgrade ob-R gene expression. High leptin levels can lead to malnutrition. The leptin receptor is a cytokine receptor and belongs to the classⅠcytokine receptor family. The Ob-R is alternately spliced into at least six transcripts. Ob-Rb is essential in mediating most of the biologicaleffects of leptin. Ob-Rb is highly expressed in the hypothalamus, belonging to long receptor for length of its cytoplasmic tail. Leptin releasing to the blood was transported to in the cerebrospinal fluid by the short isoform (Ob-Ra) which is is highly expressed in the choroid plexus where it is likely to function as a transporter across the blood-brain barrier. Leptin binding to hypothalamic leptin receptors activates Janus kinase2/signal transducers and activators of transcription3(JAK2/STAT3). Activated STAT3 dimerize and translocate to the nucleus, where specific gene responses are licited. By this way, leptin reduces appetite.In addition to JAK/STAT pathway effectors, there are negative regulator: SOCS (suppressors of cytokine signaling) and PIAS (protein inhibitors of activated stats), which reverse the activity of the JAK/STAT. The SOCS complete a simple negative feedback loop in the JAK/STAT circuitry:activated STATs stimulate transcription of the SOCS genes and the resulting SOCS proteins bind phosphorylated JAKs and their receptors to turn off the pathway, there is evidence that STATs can be modified by sumoylation. The STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. SOCS3 and PIAS3 proteins are members of the family of cytokine-inducible inhibitors of signaling, which are activated after activation of the JAK2-STAT3 pathway specifically by leptin and which switch off cytokine signal transduction.Medical nutrition therapy is important in malnutrition of CRF patients. In western medicine, Ketosteril is main medicine treatment on malnutrition of CRF patients, but it is limit to curative effect and its price is expensive. TCM has better effects on malnutrition of CRF patients, but mechanisms of TCM is not explored. Capusle of SSYZ is experiential compound that is placed by supervisor Wei Lian-bo. It was tested that SSYZ can impove obviously malnutrition of CRF rats and can decline leptin contents in clinical and animal researches. High leptin levels that can lead to malnutrition widely occur in CRF patients. Leptin activates JAK2/STAT3 by binding to hypothalamic leptin receptors. SOCS3 and PIAS3 proteins are members of the family of cytokine-inducible inhibitors of signaling. Recently, Researches indicate excessive leptin concentrations can activate of Ob—Rb, and downgrade expression of NPY, leading to malnutrition. Based on these, We make CRF with malnutrition model, observing effect of leptin activates JAK2/STAT3 in CRF rats with malnutrition. And we hypothesis whether SSYZ can regulate signal transducer proteins, whether SSYZ can prevent from signal transducer and downgrade expression of Ob-Rb, and whether SSYZ can decline leptin concentrations and improve malnutrition. The purpose is to explore the possible mechanisms of SSYZ on improving malnutrition in CRF rats.In this study, SD rats were received 5/6 nephrectomy or Adenine fed for preparation of CRF models, Simultaneously 4%casein fed. the general state, the blood parameters, like blood urea nitrogen (BUN), serum creatinine (SCr), serum albumin(ALB), haemoglobin (Hb), and 24 hour urineprotein (24hUpro) were detected. We observed that weigh, ALB and Hb in model group were obviously declined, while BUN, SCr and 24hUpro were obviously increased, contrast to normal group. It was proved that CRF rats had malnutrition, the same as before literature. Malnutrition status in CRF rats by 5/6 nephrectomy began at the end of 10-week when weigh reduced 20%contrast to normal group. Malnutrition status in CRF rats by Adenine fed began at the end of 8-week when weigh reduced 20%contrast to normal group. Model Rats in condition were randomly sorted into the following groups. Normal control group(NC), CRF control group (CC), Ketosteril group(KT), ssyz group(SSYZ). All rats were treated with corresponding drugs fo 4 weeks. During and after the treatment, the general state, the blood parameters, like BUN, SCr, ALB, Hb, 24hUpro and leptin contents were detected. The hypothalamus of the rats were used for the study of Ob-Rb gene expression and expression of STAT3, SOCS3 and PIAS3 prtoteins, leptin contents was assayed using radioimmunoassay. Ob-RbmRNA levels were detected by semi-quantitative RT-PCR. STAT3, SOCS3 and PIAS3 prtoteins were detected by immunochemistry or westernblot. The kidenys of the rats were used for the study of nephron pathology. The changes of renal tissue morphology in experimental CRF rats with malnutrition were observed by optical microscope, immunofluorescence, and electric microscope.SSYZ and Ketosteril could improve the general state, ALB and Hb contents. Besides, BUN, Scr contents and 24hUpro concentrations were decreased. In improving the general state, ALB and Hb contents, There were no differentiae between SSYZ and Ketosteril groups. In decreasing BUN, Scr contents and 24hUpro concentrations, There were big differentiae between SSYZ and Ketosteril groups (P<0.05, P<0.01). We observed that the leptin contents and Ob—Rb gene expression of CRF rats were significantly elevated (P<0.001), SSYZ could downgrade the leptin contents and OB—Rb gene expression (P<0.01, P<0.001). The STAT3 immunoreactivities were inantly localized in the neuronal cytoplasm in hypothalamic cell. The STAT3 immunoreactivities of CRF rats were significantly upgraded (P<0.001), SSYZ could downregulate the STAT3 immunoreactivities (P<0.001). The SOCS3 immunoreactivities were inantly localized in the neuronal cytoplasm in hypothalamic cell as well as neuraxon and dendritic fibers. The PIAS3 immunoreactivities were inantly localized in the neuronal cytoplasm in hypothalamic cell. The expression of SOCS3 and PIAS3 protein of CRF rats were significantly elevated (P<0.001), SSYZ could elevate the expression of SOCS3 and PIAS3 protein (P<0.05). There were differentiae among SSYZ and Ketosteril groups (P<0.001). In CC group, What were seen by optical microscope that mesangial area of renal glomerulus broadening, even protein substances with PAS postive markebly increasing, extracellular matrix of glomerulus enlarging in number, mesangial cell increasing, GBM thickening and so on. The results observed by transmission electric microscope showed that GBM hadbeen thick, some of which were obscure, and epithelium hernia mixed in full or a part, besides, the hiatus of filtering membrane broadened, so did mesargial area, and the number of mesangial cell increased. The pathlogical changes of SSYZ group treated by SSYZ capsule for 4 weeks allieved more obviously than CC group The experimental results infered that SSYZ capsule could ameliorate pathologic change in CRF rats with malnutrition obviously.In conclusion, the results of the present study provide some evidences that SSYZ and Ketosteril can obviously improve malnutrition. There were no differentiae between SSYZ and Ketosteril groups. SSYZ can enhance expression of SOCS3 and PIAS3 proteins, downgrade expression of STAT3 protein, inhibit the activators of JAK2/STAT3, downregulate OB-Rb gene expression, and decline leptin con centratins. These effects maybe one of the mechanisms that SSYZ adjusts malnutrition of CRF rats. SSYZ had better effect on improving renal lesions than KT.

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