الفهرس 
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Abstract
Acute Renal Failure (ARF) Is A Life-Threatening Disease characterized By A Reduction Of Renal Function In The Form Of Decrease In Glomerular Filtration Rate (GFR) As Well As Elevation In Serum Creatinine, Blood Urea Nitrogen (BUN) And Oliguria. In The Current Study, ARF Was Induced Experimentally In Mice By Cisplatin (CP) A Potent And Widely Used Anti-Cancer For A Vast Range Of Solid Cancers, However, It Causes Renal Toxicity. In The Current Study, We Investigated The Role Of CXCL16/ADAM10 And Coagulation System Activation In The Pathogenesis Of Acute Renal Failure Induced By CP And The Possible Protective Effect Of Enoxaparin And Streptokinase Against Cp-Induced Induced Nephrotoxicity. Induction Of Acute Renal Failure Was Performed By Single Dose Intraperitoneal Injection Of Mice With CP (30 Mg/Kg).
The Study Was Divided Into Two Parts; The First Part Was A Time Course Study Of CP Nephrotoxicity In Which Animals Were Classified Into 6 Groups. One group Served As Control Group, While Rest Of Groups Received CP And Were Sacrificed After 6 H, 12 H, 24 H, 48 H, 72 H. The Second Part Was To Estimate The Reno-Protective Effect And The Underlying Mechanism Of Enoxaparin And Streptokinase Against Nephrotoxicity Induced By CP. Enoxaparin (500 IU/Kg, I.P.) Was Administrated Daily Seven Days Prior To CP Administration And Continued For Other Three Consecutive Days Till The End Of The Experiment. Streptokinase Treated Group; Mice Received Saline For 10 Days With Single Dose Of CP (30 Mg/Kg, I.P.) At The Seventh Day Then Single Dose Of Streptokinase (8000 IU/Kg, I.V.) 6 H Post-CP Injection And Euthanized 3 Days Post-Injection Of CP. At The End Of The Experiment, Urine Volume For 24 H Before Sacrifice Was Collected Then Animals Were Anesthetized With Light Ether And Blood Samples Were Withdrawn from The Retro-Orbital Plexus And Kidney Weight Was Recorded And Tissue Samples Were Collected.
Evaluation Of Nephrotoxicity Was Performed By Detection Of Kidney Functions Serum Markers Including Creatinine, Blood Urea Nitrogen (BUN) And Cystatin-C, And Kidney Urine Markers Including Urine Creatinine, Total Protein In Urine, Urine Volume And Glomerular Filtration Rate (GFR). Additionally, We Detected Animal Weight, Relative Kidney Weight And Renal Histological Changes. Besides Detection Of C-X-C Ligand 16 (CXCL16), A Disintegrin And Metalloproteinase (ADAM10) Cluster Of Differentiation 3 (CD3). In Addition, Inflammatory Markers As Tumor Necrosis Factor-Α (TNF-Α) And Nuclear Factor-Κb (NF-Κb). Renal Tissue Expression Of Glutathione (GSH) Content, Lipid Peroxidation Malondialdehyde (MDA) And Nitric Oxide (Nox) Production Were Determined As Oxidative Stress Markers. Side By Side, Hematological Parameters As Complete Blood Count (CBC) And Coagulation Profile Including Prothrombin Time (PT), And International Normalized Ratio (INR) Were Estimated. In Addition, Coagulation Cascade Proteins Including Tissue Factor (TF) And Fibrinogen Were Detected In Renal Tissues.
The Main Findings Of The Present Investigation Can Be Summarized As Follow:
1- Administration Of Single Dose Of CP (30 Mg/Kg, Ip) Affected Mice Weight And Relative Kidney Weight Significantly As Compared To Control Group. Additionally, CP Caused An Elevation In Kidney Relative Weight This Increment Was Significant Post 48 H And 72 H As Compared To Control. Moreover, CP Led To Destruction In Histological characters Of Renal Tissue. On The Other Hand, Pretreatment Of Mice With Enoxaparin And Streptokinase Treatment Significantly Decreased Animal Weight Loss And Relative Kidney Weight As Well As Ameliorated The Histological characters Of Renal Tissue Of Diseased Mice.
2- The Present Study Significantly Showed An Elevation Of Serum Creatinine And BUN Post 12 H Of CP Injection As Compared To Control Group. Besides, Cystatin-C And Proteinuria Significantly Increased Post 6 H Of Cisplatin Injection As Compared To Control Group. In Addition, We Also Found That CP Caused Significant Decrease In GFR And Diuresis Post 48 H And 72 H Of CP Injection. Enoxaparin And Streptokinase Improved Renal Function Tests where They Significantly Decreased Serum Creatinine, BUN, Cystatin-C And Proteinuria Levels. In Addition, They Increased Urine Volume And GFR Significantly.
3- In This Study Inflammatory Markers Showed Significantly Elevation As TNF-Α Showed Significantly Increased Post 24 H. Besides NF-Κb Showed Significant Increase Post 6 H And Then Gradually Increased Till Peaked Post 72 H As Compared To Control Group. Besides Enoxaparin And Streptokinase Significantly Decreased Inflammatory Markers Via Decrease TNF-Α And NF-Κb Signaling Pathway.
4- Immunofluorescence Staining Of Kidney Cells In CP Mice Showing Moderate To High Expression Of CXCL16, ADAM10, Ox-LDL And CD3 Post 6 H Till Peaked Post 72 H from CP Injection As Compared To Control Group. Enoxaparin And Streptokinase Decrease Expression Of CXCL16, Ox-LDL, ADAM10 And CD3.
5- Oxidative Stress Biochemical Parameters Affected Gradually Through CP-Administration. CP Caused Significant Decrease In Renal GSH Content With Significant Increase In Lipid Peroxidation And Nox Production As Compared To Normal Control. Besides Enoxaparin And Streptokinase Improved Oxidative Stress Parameters where They Significantly Increased Renal GSH Content As Well As They Significantly Decreased Lipid Peroxidation And Nox Production.
6- The Expression Of Coagulation Proteins Including TF And Fibrinogen Began To Be Up-Regulated Significantly After 6 H Of CP Injection. The Expression Of TF And Fibrinogen Proteins Showed Gradually Increased After 6 H Till 72 H Of CP Injection As Compared To Control Group. In Addition, Enoxaparin And Streptokinase Significantly Down Regulated The Expression Of Coagulation Proteins Including TF And Fibrinogen.
7- Several Changes Were Observed In CBC And Coagulation Profile Of Mice After CP-Administration. CP Showed A Significant Increase In Counts Of Wbcs, Lymphocytes, Monocytes And Granulocytes Post 48 H And 72 H from Injection. Besides, We Observed Significant Decreases In Platelets Count Post 72 H from CP Administration. In Addition, CP Caused Gradual Significant Increase In PT And INR Post 6 H from Cisplatin Administration. On The Other Hand, Treatment Of Animals With Enoxaparin And Streptokinase Significantly Decreased Count Of Wbcs, Monocytes And Granulocytes With Significant Increase In Platelets Count. Moreover, Significant Decreases In PT And INR Were Observed.
Depending On The Previous Findings, It Could Be Concluded That:
1. Cisplatin Caused Acute Renal Failure In Mice Evident Through Release Of Inflammatory Mediators, Oxidative Stress, Activation Of Blood Coagulation Pathway. Interestingly, There Is A Crucial Role Of CXCL16, ADAM10, CD3 And Ox-LDL In In The Progression Of CP Nephrotoxicity.
2. Enoxaparin And Streptokinase Cause Protective Effect Against CP Induced Nephrotoxicity While, Streptokinase Caused An Ameliorative Effect Through;
• Improvement Of Renal Functions.
• Attenuation Of Oxidative Stress And Inflammatory Cells Via Suppression Of Tumor Necrosis Factor-Α (TNF-Α) And Nuclear Factor-Κb (NF-Κb) Signaling Pathway.
• Downregulation Of Soluble CXCL16, ADAM10 And Prevented Immune Cells Infiltration Such As T Cells (CD3) Into The Renal Tissues.
• Attenuation Of Ox-LDL And Its Scavenger Receptor Transmembrane CXCL16.
• Attenuation Of Coagulation Cascade Through Low Expression Of TF, Fibrinogen, Inhibition Of Prothrombin Time And INR.
• Suppression Total Wbcs Including Lymphocyte, Granulocyte And Monocyte.
• Protection Against Histopathological Effects Of CP-Induced Nephrotoxicity.
Enoxaparin And Streptokinase Seem To Be Promising Therapeutic Agents For Acute Renal Failure Protection And Treatment. Further Clinical Trials Are Needed To Prove These Findings On Human Beings.