The Expression and Molecular Mechanisms of Matrix Metalloproteinase-9 and Vascular Endothelial Growth Factor in Renal Interstitial Fibrosis in Rats.

To explore a new approach for the treatment of renal interstitial fibrosis (RIF), we detected the expression of matrix metalloproteinase-9 (MMP9) and vascular endothelial growth factor (VEGF). Twenty-four male Sprague Dawley (SD) rats were randomly divided into 2-week normal control (2NC) group, 4-week NC (4NC) group, 2- week unilateral ureteral obstruction (2UUO) group, and 4-week UUO (4UUO) group. We performed left ureteral ligation on UUO groups. Then, we sacrificed the rats of the 2NC group and 2UUO group at 2 weeks and the other groups at 4 weeks after the surgery. Immunohistochemistry and western blot were applied to detect the expression of MMP9, VEGF, fibronectin (FN), type IV collagen (Col-IV), and transforming growth factor-ß1 (TGF-ß1). MMP9 levels reduced after UUO surgery. Its expression was less in the 4UUO group than in the 2UUO group (P<0.05). The expression of VEGF, TGF- ß1, FN, and Col-IV was higher in UUO groups than in NC groups (P<0.05). The expression of these indicators was higher in the 4UUO group than in the 2UUO group (P<0.05). In the correlation analysis, MMP9 levels in UUO groups had a negative correlation with the expression of TGF-ß1, VEGF, Col-IV, FN, and RIF index (all P<0.05). In UUO groups, VEGF levels had a positive correlation with the expression of TGF-ß1, Col-IV, FN, and RIF index (all P<0.05). In conclusion, with the aggravation of RIF lesions, MMP9 levels decreased, and VEGF levels increased. Whether there is a mutual inhibition relationship between them remains to be confirmed by further experiments.

The Preventive Effect of Endostar on Radiation-Induced Pulmonary Fibrosis.

BACKGROUND: Radiation-induced pulmonary fibrosis (RIPF) is a long-term complication of thoracic radiotherapy without effective treatment available. OBJECTIVE: This study aimed to establish a RIPF mouse model and explore the therapeutic effects and mechanisms of recombinant human endostatin (Endostar). METHODS: C57BL/6 mice received a 16-Gy dose of X-rays to the whole thorax with or without the administration of Endostar for 24 weeks. RESULTS: Radiation-induced body weight loss was partially attenuated by Endostar (P<0.05). Endostar significantly reduced alveolar inflammation (P<0.05) and pulmonary fibrosis (P<0.001), as indicated by a decrease in the expression levels of collagen I and collagen IV in lung tissue (both P<0.001). Angiogenesis (as shown by CD31 immunohistochemistry) was also decreased (P<0.01). In irradiated mice, Endostar inhibited the transforming growth factor-ß1 (TGF-ß1)/drosophila mothers against the decapentaplegic 3 (Smad3)/extracellular regulated protein kinases (ERK) signaling pathway (all P<0.05). In vitro, Endostar treatment decreased the radiation-induced expression of TGF-ß1, vascular endothelial growth factor (VEGF), p-Smad3, and p-ERK in alveolar epithelial cells and vascular endothelial cells (all P<0.05). CONCLUSION: Endostar could alleviate RIPF through decreased antiangiogenic activity and inhibition of the TGF-ß1/Smad3/ERK pathway.

Immune responses to injury and their links to eye disease.

The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact both the anterior and posterior segment and lead to reduced quality of life and blindness. Here we focus attention on the role that inflammation and fibrosis play in the progression of age-related pathologies of the cornea and the lens as well as in glaucoma, the formation of epiretinal membranes, and in proliferative vitreoretinopathy.

PTTG1 knockdown enhances radiation-induced antitumour immunity in lung adenocarcinoma.

AIM: Ionizing radiation (IR) can induce local and systemic antitumour immune responses to some degree and augment immunotherapeutic efficacy. IR may also increase residual tumour cell invasion and elicit immunosuppression in the tumour microenvironment (TME). It remains poorly understand, whether IR leads to immune negative response or invasive capacity increases in lung adenocarcinoma (LAC). MATERIALS AND METHODS: RNA interference (RNAi) was used to silence pituitary tumour-transforming gene-1 (PTTG1) and SMAD3 expression in LAC cells. A coculture system of tumour cells and PBMCs was constructed. Cells were exposed to different doses (0, 4 and 8 Gy) of X-ray irradiation. Flow cytometric analysis and Transwell assays were applied. An orthotopic Lewis lung cancer (LLC) mouse tumour model was established. Bioluminescence imaging (BLI) was used. LLC tumours were exposed to a single 15 Gy dose of X-ray irradiation. KEY FINDINGS: PTTG1 knockdown reinforced the inhibitory effect of IR on the invasive ability of A549 cells and enhanced the antitumour T cell immunity induced by IR via the transforming growth factor-ß1 (TGF-ß1)/SMAD3 pathway. Positive antitumour immune response and immunosuppression were simultaneously triggered by a single 15 Gy dose of local tumour irradiation. PTTG1 knockdown weakened invasive capacity and promoted the immune response balance induced by IR to tilt towards active immunity, which contributed to reduce metastasis and prolonged overall survival (OS) in orthotopic LLC tumour-bearing mouse. SIGNIFICANCE: Targeted blockade of PTTG1 and the TGF-ß1/SMAD3 pathway may ameliorate the immunosuppressive TME and enhance the systemic antitumour immune response induced by a single high-dose IR treatment.

The influences of TGF-ß1 upon the human adenocarcinoma cell of lung A549 and cellular immunity.

BACKGROUND: The cellular immunity of lung cancer patients is mainly the immune response of T cells, which plays an important role in tumour cell killing and immune surveillance. Transforming growth factor 1 (TGF-ß1) is secreted by tumour cells that can suppress the immune response and is an important group of immune down-regulation factors. Our study aims to investigate the effect of TGF-ß1 on the morphology and cellular immune function of A549 and peripheral blood mononuclear cells (PBMCs). METHODS: A549 cell line was cultured, PBMCs were cultured with different concentrations of TGF-ß1, and the morphology of A549 cells and PBMCs were seen. The levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and TNF and the numbers of CD3, CD4, CD8, CD4/CD8, and CD3 CD25 and CD4 CD25 in PBMCs were detected. RESULTS: During co-culture of A549 with PBMCs, TGF-ß1 can induced A549 showing epithelial-to-mesenchymal transition, enhanced its ability of migration and infiltration. Simultaneously, TGF-ß1 can depressing the growth and proliferation of PBMCs, inhibiting T-cell activation, and accelerating the PBMCs apoptosis. TGF-ß1 can inhibits A549 Th1 related-cytokines, enhance Th2 related-cytokines, cause the disorder of Th1/Th2, resulting in the Th1 cellular dominate immunity decline. CONCLUSIONS: TGF-ß1 may affect the secretion of related cytokines, hinder the activation of T lymphocytes, destroy the immune surveillance and killing effect of the body, and thus inhibit the cellular immunity.

Effect of Oral Losartan on Orthobiologics: Implications for Platelet-Rich Plasma and Bone Marrow Concentrate-A Rabbit Study.

Recent efforts have focused on customizing orthobiologics, such as platelet-rich plasma (PRP) and bone marrow concentrate (BMC), to improve tissue repair. We hypothesized that oral losartan (a TGF-ß1 blocker with anti-fibrotic properties) could decrease TGF-ß1 levels in leukocyte-poor PRP (LP-PRP) and fibrocytes in BMC. Ten rabbits were randomized into two groups (N = 5/group): osteochondral defect + microfracture (control, group 1) and osteochondral defect + microfracture + losartan (losartan, group 2). For group 2, a dose of 10mg/kg/day of losartan was administrated orally for 12 weeks post-operatively. After 12 weeks, whole blood (WB) and bone marrow aspirate (BMA) samples were collected to process LP-PRP and BMC. TGF-ß1 concentrations were measured in WB and LP-PRP with multiplex immunoassay. BMC cell populations were analyzed by flow cytometry with CD31, CD44, CD45, CD34, CD146 and CD90 antibodies. There was no significant difference in TGF-ß1 levels between the losartan and control group in WB or LP-PRP. In BMC, the percentage of CD31+ cells (endothelial cells) in the losartan group was significantly higher than the control group (p = 0.008), while the percentage of CD45+ cells (hematopoietic cells-fibrocytes) in the losartan group was significantly lower than the control group (p = 0.03).

Analysis of the clinical effects of the combination of mycophenolate mofetil with either tacrolimus or cyclophosphamide

OBJECTIVES: Here, we aimed to compare the clinical effects of mycophenolate mofetil combined with either tacrolimus or with cyclophosphamide on lupus nephritis (LN) and to analyze their influence on the expression of cystatin C and on transforming growth factor-1 (TGF-β1). METHODS: A total of 234 patients were randomly divided into two groups: group A, for mycophenolate mofetil combined with tacrolimus (n=117) and group B, for mycophenolate mofetil combined with cyclophosphamide (n=117). The enzyme-linked immunosorbent assay was adopted to detect the expression levels of serum TGF-β1 and cystatin C before and after treatment. RESULTS: The total effectiveness rate in group A was much higher than that in group B. The times of effectiveness and effect validity in group A were much lower than those in group B. The expression levels of serum TGF-β1 and cystatin C decreased slightly after treatment in the two groups, and those of group A were much lower than those of group B. CONCLUSIONS: The combination of mycophenolate mofetil and tacrolimus showed better clinical efficacy on LN and was safer than that of mycophenolate mofetil and cyclophosphamide. Moreover, the drug combination of mycophenolate mofetil and tacrolimus greatly reduced the expression levels of serum TGF-β1 and cystatin C.

Hepatocellular Carcinoma: Etiology and Current and Future Drugs.

Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.

Starvation-induced autophagy promotes the invasion and migration of human bladder cancer cells via TGF-ß1/Smad3-mediated epithelial-mesenchymal transition activation.

The biological characteristics of bladder cancer include enhanced invasion and migration, which are the main causes of death in patients. Starvation is a typical feature of the bladder cancer microenvironment and can induce autophagy. Autophagy has an important relationship with the invasion and migration of tumors. However, the role of autophagy in the invasion and migration of bladder cancer cells remains unclear. Hence, the aim of the current study was to clarify this role and underlying mechanism. In this study, we found that starvation enhanced the epithelial-mesenchymal transition (EMT)-mediated invasion and migration of T24 and 5637 cells while inducing autophagy. The inhibition of autophagy with chloroquine (CQ) or 3-methyladenine (3MA) decreased EMT-mediated invasion and migration. In addition, the expression of transforming growth factor 1 (TGF-ß1) and phosphorylated Smad3 (p-Smad3) increased after starvation. The inhibition of autophagy with CQ or 3MA also decreased the expression of TGF-ß1 and p-Smad3. The inhibitor of TGF-ß receptor sb431542 also inhibited the invasion, migration, and EMT of T24 and 5637 cells during starvation. Furthermore, recombinant TGF-ß1 induced autophagy and inhibition of the TGF-ß/Smad signaling pathway with sb431542 suppressed autophagy. In summary, our results suggested that autophagy promotes the invasion and migration of bladder cancer cells by inducing EMT through the TGF-ß1/Smad3 signaling pathway. Moreover, autophagy and TGF-ß1 can form a positive feedback loop to synergistically promote invasion and migration. Thus, our findings may provide a theoretical basis for the prevention of invasion and migration in bladder cancer.

Effects of brd4 gene on apoptosis and p38mapk signaling pathway of cardiomyocytes induced by tgf-pi / 吉林大学学报(医学版)

Objective: To investigate the effect of bromodomain-containing protein 4 (BRD4) gene on the apoptosis of cardiomy

Experimental study on TGF-ß1-mediated CD147 expression in oral submucous fibrosis.

OBJECTIVE: Although previous evidence indicates that CD147 is closely involved in the progression of organ fibrosis and various signaling pathways have been proven to regulate its expression, the role of CD147 in oral submucous fibrosis (OSF) remains largely unknown. METHODS: In this study, we investigated the expression of CD147 and transforming growth factor ß1 (TGF-ß1) in human samples of an OSF tissue array by immunohistopathology. Pearson's correlation analysis was conducted to explore the correlation between CD147 and TGF-ß1. Immunofluorescence and Western blotting were used to investigate to levels of CD147 in Human Oral Keratinocytes (HOKs) followed by TGF-ß1 or LY2157299, an inhibitor of TGF-ß1 receptor and arecoline stimulation. RESULTS: We found that CD147 was highly expressed in both HOKs and the fibrotic oral mucosa and that this expression was correlated with TGF-ß1 expression. Additionally, CD147 levels were significantly associated with the fibrosis stage. The TGF-ß1 signaling pathway was found to be mainly responsible for CD147 up-regulation after arecoline treatment whereas inhibition of TGF-ß1 down-regulated CD147 expression. CONCLUSION: Our findings suggest arecoline promotes CD147 expression via the TGF-ß1 signaling pathway in HOKs, whereas overexpression of CD147 may promote OSF progression.

Expression of transforming growth factor 1 and bone morphogenetic protein 9 in human nonunion tissues and its clinical significance / 中南大学学报(医学版)

Objective:To examine the expression of transforming growth factor I(TGF-β1) and bone morphogenetic protein-9 (BMP-9) in human nonunion tissues,and to evaluate the clinical significance.Methods:The number of hypertrophic nonunion tissue samples and atrophic nonunion tissue samples were collected from Department of Orthopedics,the Second Xiangya Hospital of Central South University and Suzhou Kowloon Hospital Affiliated to School of Medicine of Shanghai Jiao Tong University between 2010 and 2014.Semi-quantification of SP immunohistochemical method and pathological image analysis software IPP6.0 were used to analyze the expression of TGF-β1 and BMP-9.Nonunion type,patients' age and nonunion time were statistical analyzed.Results:The absorbance values of TGF-β1 and BMP-9 in the hypertrophic nonunion tissues were 0.3236±0.0390 and 0.1337±0.0400,respectively;while the absorbance values of TGF-β1 and BMP-9 in the atrophic nonunion tissues were 0.3191±0.0369 and 0.1373±0.0423,respectively,with no significant difference between the two types of tissues (both P＞0.05).There was also no significant difference in patients' age and bone nonunion time between them (all P＞0.05).Conclusion:There is no significant difference in osteogenic potential between the hypertrophic nonunion tissues and the atrophic nonunion tissues.

Intervention effect and mechanism of polyguanylic acid on pulmonary fibrosis in silica-exposed rats / 中国职业医学

OBJECTIVE: To observe the intervention effect of polyguanylic acid( Poly G) on silicosis fibrosis in rats and to explore its possible mechanism. METHODS: Specific pathogen free adult male SD rats were randomly divided into 6 groups:control group,silicosis model group and 4 intervention groups( intervention group 1,2,3 and 4),with 5 rats in each group. Except for the control group,the other 5 groups were treated with 1. 0 m L silica suspension( 50. 0 g / L mass concentration) by intratracheal intubation,four intervention group was given by intraperitoneal injection of 1,2,3 and 4doses of Poly G at 2. 5 mg / kg body weight after establishing the model for 1 to 21 days. All rats were sacrificed 28 days after silicosis model establishment. Lung pathological changes were observed and the pulmonary fibrosis was evaluated by Ashcroft scores. The expression of Macrophage receptor with collagenous structure( MARCO),transforming growth factor-β1( TGF-β1),E-cadherin,Vimentin and α-smooth muscle actin( α-SMA) protein were detected by western blot.RESULTS: In the model group,a large number of dust cell aggregates were found in the alveolar cavity and diffuse collagen deposition appeared in the pulmonary interstitial,indicating that silicosis model was successfully constructed. The alveolar structure of the single dose intervention group was integral and the degree of fibrosis was significantly less than that of the silicosis model group. Compared with the control group,MARCO,TGF-β1,Vimentin and α-SMA expression levels of silicosis model group were increased,the expression level of E-cadherin decreased, the difference was statistically significant( P < 0. 05). Compared with the silicosis model group,TGF-β1,Vimentin and α-SMA expression levels of single dose intervention group decreased,E-cadherin expression level increased,the difference was statistically significant( P < 0. 05). The dose-response relationship could not perceived between the Poly G intervention times and the Ashcroft scores or the protein expression levels of MARCO,TGF-β1,E-cadherin,Vimentin and α-SMA respectively. CONCLUSION: Poly G can effectively reduce lung inflammation and fibrosis in rats. The effect of single dose intervention( 2. 5 mg / kg body weight,intraperitoneal injection) at the first day after silica exposure is the best. The mechanism of action may be related to the low-does Ply G which can inhibit the epithelial-mesenchymal transition and then result in the decrease of collagen synthesis.

The role of thrombospondin-1 in corneal wound healing / 中华实验眼科杂志

Thrombospondin-1 (THBS-1),a kind of extracellular matrix proteins,whose biological action played an important role in corneal wound healing has became a research highlight.The currently research findings showed that THBS-1 could promote the healing of epithelium,stroma and endothelium through activating the transforming growth factor-β1 (TGF-β1) which can accelerate cell proliferation,promote stroma forming and inducing cell migration.It is worthful in clinical treatment of all kinds of corneal wound healing.Now we summarized the research developments which have been acquired in the field recently in this article.

Interleukin 10 (IL10) and transforming growth factor 1 (TGF1) gene polymorphisms in persistent IgE-mediated cow's milk allergy

OBJECTIVES: The aim of this cross-sectional study was to evaluate whether interleukin 10 (IL10) and transforming growth factor β1 (TGFβ1) gene polymorphisms were associated with persistent IgE-mediated cow's milk allergy in 50 Brazilian children. The diagnostic criteria were anaphylaxis triggered by cow's milk or a positive double-blind, placebo-controlled food challenge. Tolerance was defined as the absence of a clinical response to a double-blind, placebo-controlled food challenge or cow's milk exposure. METHOD: The genomic DNA of the 50 patients and 224 healthy controls (HCs) was used to investigate five IL10 gene polymorphisms (-3575A/T, -2849A/G, -2763A/C, -1082G/A, -592C/A) and one TGFβ1 polymorphism (-509C/T). RESULTS: Among the five IL10 polymorphisms analyzed, homozygosis for the G allele at the -1082 position was significantly higher in the patients compared with the healthy controls (p = 0.027) and in the persistent cow's milk allergy group compared with the healthy controls (p = 0.001). CONCLUSIONS: Homozygosis for the G allele at the IL10 -1082G/A polymorphism is associated with the persistent form of cow's milk allergy. .

The structural network of inflammation and cancer: merits and challenges.

Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88.

Transforming growth factor-1 promotes the transcriptional activation of plasminogen activator inhibitor type 1 in carcinoma-associated fibroblasts.

Carcinoma-associated fibroblasts (CAFs) play a pivotal role in promoting the growth, invasion and metastasis of tumor cells. However, to date little is known about the oncogenic mechanisms of CAFs. This study aimed to identify the microenvironmental factors involved in tumor development and progression directed by CAFs in liver metastases. Tissue samples collected from 20 patients with colorectal liver metastases were used in this study. Histological and morphological characterization of the samples was performed using hybridization and immunohistological assays. The mRNA expression of α-smooth muscle actin (α-SMA) was measured by northern blotting. The expression of plasminogen activator inhibitor type 1 (PAI-1) was measured by enzyme-linked immunosorbent assay (ELISA). As a result, co-expression of Thy-1 (CD90) and α-SMA was identified in CAFs, while normal liver samples were negative for α-SMA and Thy-1. Compared with epidermal growth factor (EGF) and tumor necrosis factor (TNF) incubation, the expression of α-SMA increased significantly following transforming growth factor-1 (TGF-1) incubation (P<0.05), while platelet-derived growth factor (PDGF) caused a significant suppression of α-SMA expression (P<0.05). PAI-1 expression was significantly lower in unstimulated fibroblasts compared to TGF-1-treated fibroblasts (P<0.01). The levels of PAI-1 transcription were significantly higher in CAFs from the patient samples compared with the healthy controls. Taken together, our findings suggest that CAFs may be important in migration, matrix degradation, invasion and angiogenesis of tumors, and TGF-1 may promote the activation of PAI-1 transcription in CAFs.

Study on the effect of microparticle platelet frozen-powder on the healing of skin wound in mouse / 中国输血杂志

0.05). Levels of TGF-?1 and PDGF in microparticle platelet frozen powder were higher than those in fresh platelet(P

Effect of Shuxuetong injection on the expressions of TGF-?_1 and Col-IV in renal tissues in diabetic rats / 重庆医科大学学报

Objective:To investigate the effect of Shuxuetong injection on the urine protein excretion changes and expressions of transforming growth factor ?(1TGF-?1)and collegen type Ⅳ(Col-Ⅳ)in renal tissues in diabetic rats.Methods:Diabetic nephropathy was induced by intraperitoneal injection of streptozotocin(STZ).Rats were randomly divided into control group,untreated DN group,Shuxuetong group and Benazepril group.Urinary albumin excretion rate(UAER),?2-microglobulin(?2-MA)and KW/BW(kidney weight/body weigh)were determined 8 weeks later.The expressions of TGF-?1 and Col-Ⅳ in renal tissues were determined by using immunohistochemical methods.Results:After interference,compared with the untreated DN group,UAER,?2-MA,KW/BW in the Shuxuetong group were significantly down-regulated(P

Protective Effect of the Extract of Ginkgo biloba on the Kidney in Diabetic Rats / 中国药房

OBJECTIVE:To investigate the effect of extract of Ginkgo biloba(EGb) on levels of Endothelin-1(ET-1) and transforming growth factor ?1(TGF-?1) in renal tissue of diabetic rats.METHODS:Twenty-four male Sprague-Dawley rats were randomly divided into three groups:normal control group,diabetic model group and EGb-treated group.The levels of blood glucose,insulin,total cholesterol(TC),total triglycerides(TG),creatinine clearance(Ccr),urinary albumin excretion(UAE),and urinary ?2-MG were measured after 8-week corresponding treatment.Expression of SET-1,UET-1,and RET-1 was examined by radioimmunoassay technique.Expression of STGF-?1 and UTGF-?1 in serum and urine was examined by enzyme linked immunosorbent assay(ELISA).RESULTS:The concentrations of blood glucose,blood insulin,TC and TG increased significantly in diabetic group,which were down-regulated by EGb.Levels of ET-1 and TGF-?1.in both blood and urine and the ET-1 level in renal tissues were significantly higher in diabetic model group than in normal control group(P