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العنوان
Study of the Effect of Statins on Altered Kidney Function in Experimental Type 1 Diabetes in the Rat /
المؤلف
El Deeb, Asmaa Mohamed Kamal Zaki.
هيئة الاعداد
باحث / أسماء محمد كمال زكي الديب
مشرف / عماد الدين عبد الحميد البسيونى
مشرف / رويدا رفعت شحاتة
مناقش / منى عبد الرازق سلامة
مناقش / حسني أحمد محمد عليوة
الموضوع
Pharmacology and Experimental Therapeutics. Pharmacology.
تاريخ النشر
2019.
عدد الصفحات
102 p. :
اللغة
الإنجليزية
الدرجة
ماجستير
التخصص
الصيدلة ، علم السموم والصيدلانيات (المتنوعة)
تاريخ الإجازة
16/3/2019
مكان الإجازة
جامعة الاسكندريه - معهد البحوث الطبية - Pharmacology
الفهرس
Only 14 pages are availabe for public view

from 102

from 102

Abstract

The impact of diabetes on health resides in a series of complications that characterize this disease. Absolute or relative insufficient insulin functions can induce consequences of complex metabolic disorder. Kidney damage represents one of the most important consequences. Complex etiologic factors can contribute to abnormal renal functional or structural alterations in the diabetic state, which manifest in eventual irreversible renal damage. However, the pathogenesis, triggering factors and underlying mechanisms behind the development of diabetes and its complications are not very clear.
There are reports that some statins have renoprotective action. Such action is probably mediated by pleiotropic mechanisms, independent of their lipid lowering effects, including actions on cell proliferation, apoptosis, oxidative stress and inflammation, which may augment the progress of diabetic nephropathy. The present study aimed to investigate the pleiotropic effects of simvastatin and rosuvastatin on the kidney of streptozotocin (STZ)-induced diabetic rats.
Methods: The present study was carried out on thirty two adult males of Sprague-Dawley rats weighing 140-150 g each. Animals were kept under observation for one week prior to the study with free access to feed and water. Rats were housed under controlled conditions of light illumination, relative humidity and temperature. All animal procedures were performed according to an approved protocol and in accordance with regulations of the Committee on the Care and Use of Experimental Animals of Alexandria University.
Drug treatments:
Diabetes was induced by a single 65mg/kg intraperitoneal injection of streptozotocin (STZ) into 12 hour food-deprived rats. Induction of diabetes was confirmed by a blood glucose level above 200 mg/dL 48 hours after streptozotocin injection. Blood samples were withdrawn from the tail vein. Statins were dissolved in 2% gum acacia and treatment was started 3 weeks after STZ injection when the kidney should have recovered from the acute mild nephrotoxic effect of STZ.
Cystatin-c as an estimator of glomerular filtration rate, transforming growth factor-β (TGF-β) as one of the growth factors implicated in diabetic nephropathy pathogenesis and 8-hydroxydeoxyguanosine (8-OHdG) as a marker for oxidative DNA damage were assayed in the serum. Cytokines, including IL-1β, IL-10 and PGE2, and oxidative stress markers MDA, GSH, GSSG, GSH/GSSG ratio and tGSH as well as cytochrome c as an indicator of apoptosis were determined in the kidney homogenate.
Disturbances in the levels of inflammatory, apoptotic and oxidative stress markers were observed as a result of induction of diabetes, which were partly corrected by treatment with the used statins. The mean level of IL-1β, which is an important mediator of the inflammatory response in diabetic rats, was several times that of normal controls. These high levels were attenuated approximately to the same levels by treatment with either simvastatin or rosuvastatin. The increase in IL-1β was accompanied by a significant increase in the anti-inflammatory IL-10. It is probable that such increase represented a
Summary
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defense mechanism against the high levels of the proinflammatory mediators in the diabetic kidney partly by down regulation of proinflammatory cytokines and their receptors and upregulation of cytokine inhibitors. Treatment with the statins caused a significant decrease in IL-10 parallel to the decrease in IL-1β, with rosuvastatin more effective than simvastatin,
Induction of diabetes caused PGE2 to reach higher levels in the kidneys of the diabetic rats, which were partially corrected by treatment with statins. The overproduction of PGE2 plays an important role in the end organ damage in diabetes. It was suggested that IL-1 preferentially stimulates the production of prostaglandins and many of the biological activities of IL-1 are probably due to increased PGE2 production. The decrease of IL-1 level following treatment with both statins used was accompanied by a similar fall in PGE2. This may be a pointer for possible attenuation of the progression of kidney damage.
Increased level of TGF- β, may enhance apoptosis in diabetic nephropathy and increases intracellular ROS in mesangial and tubular epithelial cells. Oxidative stress is clearly shown in the diabetic kidney in the present study by decreased levels of GSH and GSH/GSSG ratio. On the other hand, there are substantial increases in the levels of GSSG and MDA. These changes were shifted toward the non-diabetic values following treatment with both statins used. However, the level of total glutathione was neither modified by induction of diabetes nor by treatment with statins. This may indicate that the synthesis of glutathione was not affected by these manipulations and the problem lies with the reduction of GSSG.
Fragmentations of DNA, as shown by the serum level of 8-OHdG and the apoptotic marker cytochrome c were highly elevated in diabetic rats. Apoptosis contributes to the development of diabetic nephropathy. It was suggested that increased oxidative stress and increased levels of inflammatory cytokines may also enhance the apoptosis levels in diabetic nephropathy. When the cell detects an apoptotic stimulus, such as DNA damage or metabolic stress, the intrinsic apoptotic pathway is triggered and mitochondrial cytochrome c is released into the cytosol. It has been suggested that cystatin c might predict the risk of developing chronic kidney disease. Attenuation of the high levels of these parameters is therefore expected to signal improvement of renal function and slowing down of the progression of kidney disease.
Conclusion: Treatment of diabetic rats with simvastatin or rosuvastatin caused the determined inflammatory, oxidative stress and apoptosis markers to shift toward near normal values and therefore probably slowing down the progression of renal dysfunction in this model.