Deneysel diyabetik nefropatide irbesartan ve antioksidan tedavilerin karşılaştırılması
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Tarih
2008
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info:eu-repo/semantics/openAccess
Özet
Endüstriyel yaşamla birlikte yüksek morbidite ve mortalite oranları ile seyreden Diyabetes Mellitus ve buna bağlı diyabetik nefropati sıklığı hızla artmaktadır. Yüksek glisemi ve metabolitlerine bağlı olarak artan oksidatif stres ve renin angiotensin sistem aktivasyonu ve azalaBn hücre içi ATP pompa zayıflığı, Diyabetes Mellitusa bağlı organ bozulmalarından sorumlu tutulmaktadır. Yapılan çalışmalarda renin angiotensin sistem aktivasyonunu baskılayıcı angiotensin II AT 1 reseptör blokerleri ile diyabetik nefropati gelişiminin yavaşladığı, antioksidan olan alfa lipoik asit ile renal bozulmanın yavaşladığı, L-karnitin ile ATP'nin arttığı, lipid peroksidasyonunun azaldığı gözlenmiştir. Ancak, AT1 reseptör blokerleri ile alfa lipoik asit ve L-karnitin kombinasyon tedavilerini inceleyen çalışmaya ulaşamadık. Biz de çalışmamızda streptazosin 45 µg/kg ile deneysel tip 1 Diyabetes Mellitus oluşturulan ratlarda kan basıncını düşürmeyen dozda AT 1 reseptör blokeri olan 5mg/kg irbesartan, antioksidan olan 100 mg/kg alfa lipoik asit, irbesartan + alfa lipoik asit ve irbesartan + 150 mg L-karnitini oral yoldan 12 hafta süre ile verdik. 12 hafta sonunda ratlar metabolik kafese alınıp 24 saatlik idrar toplanarak sakrafiye edildi. İdrar ve kanda biyokimyasal incelemeler yapıldı. Böbrek korteks kesitlerinde peryodik asit shift, transforming growth factor beta-1 ve indüklenebilir nitrik oksit sentaz birikimleri incelendi. Sağlıklı kontrol ile Diyabetes Mellitus grupları ve hasta kontrol ile tedavi gruplarının verileri karşılaştırıldı. Tüm Diyabetes Mellitus gruplarında istatikasel olarak anlamlı derecede olmayan glomerüler filtrasyon hızı artışının yanında kanda glukoz, HbA1c, üre değerlerinde de artış görüldü. Alfa lipoik asit ve irbesartan + alfa lipoik asit gruplarında anlamlı derecede kreatinin artışının yanı sıra, idrarla atılan protein ve albümin atılımındaki belirgin artış ile renal fonksiyon ve yapısal bozukluğun olduğu gözlendi. Renal korteks kesitlerinde peryodik asit shift boyamada glomeruler ve tubuler bazal membranlarda belirgin kalınlaşmalar ve mezengial hücrelerde transforming growth factor beta-1 ve indüklenebilir nitrik oksit sentaz artışı ile renal yapısal bozulmanın geliştiği gözlendi. Hasta kontrol grubuna göre irbesartan + alfa lipoik asit verilen grupta idrar volümünde anlamlı; glomerüler filtrasyon hızı, üriner protein ve albüminatılımında anlamlı derecede olmayan düşme; peryodik asit shift, transforming growth factor beta-1 ve indüklenebilir nitrik oksit sentaz birikiminde hafif azalma gözlendi. İrbesartan + alfa lipoik asit ve irbesartan + L-karnitin gruplarında anlamlı derecede glomerüler filtrasyon hızında azalma saptandı. Aynı kombinasyon gruplarında anlamsız derecede üriner protein atılımı, üriner albümin atılımı ve idrar volüm azalması saptanırken, daha belirgin şekilde peryodik asit shift, transforming growth factor beta-1 ve indüklenebilir nitrik oksit sentaz birikiminde azalma gözlendi. Ancak tedavi gruplarında renal doku antioksidanlarında (superoksit dismutaz, glutatyon, glutatyon peroksidaz) artış ve trigliseritlerde azalma gözlenmedi. Sonuç olarak bulgularımız AT1 reseptör blokerlerinin, oksidatif stresin organ hasarı gelişiminde önemli role sahip olduğu Diyabetes Mellitus hastalarında antioksidanlarla birlikte verilmesi halinde; renal koruyucu etkilerini güçlendirdiğini göstermektedir
With industrial life becoming common, the frequencies of diabetes mellitus and secondary diabetic nephropathy which have high morbidity and mortality have been increasing. High glycemia and oxidative stress secondary to an increase in metabolites, the activation of the renin angiotensin system and the weakness of the less active intracellular ATP pump are hold responsible for organ dysfunction secondary to diabetes mellitus. Studies have shown that Angiotensin II AT 1 receptor blockers which suppress the activation of the renin angiotensin system slow down the development of diabetic nephropathy, the antioxidant alpha lipoic acid slows down renal detorioration, L-carnitine increases ATP and decreases lipid peroxidation. However, we could not find the study which investigated the combination of AT 1 receptor blockers, alpha lipoic acid and L-carnitine. In our study, we administered streptozocin 45mg/kg and the AT 1 receptor blocker irbesartan at a dose of 5 mg/kg which did not decrease blood pressure to rats with experimental type 1 diabetes mellitus, the antioxidant alpha lipoic acid at a dose of 100 mg/kg, irbesartan+alpha lipoic acid and irbesartan+L-carnitine orally for 12 weeks. At the end of the 12 weeks, the rats were put into metabolic cages and sacrificed after the collection of a 24 hour urine sample. Biochemical tests were carried out in urine and blood. The accumulation of periodic acid schiff, transforming growth factor beta-1 and inducible nitric oxide synthase werw investigated in sections of the renal cortex. Data of the healthy control and diabetes mellitus groups, versus of the patient controls and treatment groups were compared. In all diabetes mellitus gruops, there was a nonsignificant increases in glomeruler filtration rate in addition to increases in blood glucose, HbA1c, urea levels. It was observed that creatinine level increased significantly in alpha lipoic acid and irbesartan+alpha lipoic acid groups; also, together with significant increases in urinary protein and albumin excretion, there were renal dysfunction and deterioration in structure. The staining of the sections of the renal cortex with periodic acid schiff stain showed that there were significant thickenings of the basal membranes and increase in transforming growth factor beta-1 and inducible nitric oxide synthase in the mesengial cells and that there was deterioration in renal structure. When the patient control group was compared with the irbesartan+alpha lipoic acid group, it was seen that the former had a significant decrease in urinary volume; nonsignificant decreases in glomerular filtration rate, urinary protein and albumin excretion, mild decreases in the accumulation of periodic acid schiff, transforming growth factor beta-1 and inducible nitric oxide synthase. There were significant decreases in glomerular filtration rate in irbesartan+alpha lipoic acid and irbesartan+L-carnitine groups. In the above-mentioned combination groups, there were nonsignificant decreases in urinary albumin excretion, urinary volume, and more significant decreases in the accumulations of periodic acid schiff, transforming growth factor beta-1 and inducible nitric oxide synthase. Nevertheless, there were no increase in renal tissue antioxidants (superoxide dismutase, glutathione, glutathione peroxidase) and decrease in triglycerides in treatment groups. As a result, our results indicate that AT 1 receptor blockers, when given in combination with antioxidants, enhance their renal protective effects in diabetes mellitus patients in whom oxidative stress plays an important role in the development of organ damage.
With industrial life becoming common, the frequencies of diabetes mellitus and secondary diabetic nephropathy which have high morbidity and mortality have been increasing. High glycemia and oxidative stress secondary to an increase in metabolites, the activation of the renin angiotensin system and the weakness of the less active intracellular ATP pump are hold responsible for organ dysfunction secondary to diabetes mellitus. Studies have shown that Angiotensin II AT 1 receptor blockers which suppress the activation of the renin angiotensin system slow down the development of diabetic nephropathy, the antioxidant alpha lipoic acid slows down renal detorioration, L-carnitine increases ATP and decreases lipid peroxidation. However, we could not find the study which investigated the combination of AT 1 receptor blockers, alpha lipoic acid and L-carnitine. In our study, we administered streptozocin 45mg/kg and the AT 1 receptor blocker irbesartan at a dose of 5 mg/kg which did not decrease blood pressure to rats with experimental type 1 diabetes mellitus, the antioxidant alpha lipoic acid at a dose of 100 mg/kg, irbesartan+alpha lipoic acid and irbesartan+L-carnitine orally for 12 weeks. At the end of the 12 weeks, the rats were put into metabolic cages and sacrificed after the collection of a 24 hour urine sample. Biochemical tests were carried out in urine and blood. The accumulation of periodic acid schiff, transforming growth factor beta-1 and inducible nitric oxide synthase werw investigated in sections of the renal cortex. Data of the healthy control and diabetes mellitus groups, versus of the patient controls and treatment groups were compared. In all diabetes mellitus gruops, there was a nonsignificant increases in glomeruler filtration rate in addition to increases in blood glucose, HbA1c, urea levels. It was observed that creatinine level increased significantly in alpha lipoic acid and irbesartan+alpha lipoic acid groups; also, together with significant increases in urinary protein and albumin excretion, there were renal dysfunction and deterioration in structure. The staining of the sections of the renal cortex with periodic acid schiff stain showed that there were significant thickenings of the basal membranes and increase in transforming growth factor beta-1 and inducible nitric oxide synthase in the mesengial cells and that there was deterioration in renal structure. When the patient control group was compared with the irbesartan+alpha lipoic acid group, it was seen that the former had a significant decrease in urinary volume; nonsignificant decreases in glomerular filtration rate, urinary protein and albumin excretion, mild decreases in the accumulation of periodic acid schiff, transforming growth factor beta-1 and inducible nitric oxide synthase. There were significant decreases in glomerular filtration rate in irbesartan+alpha lipoic acid and irbesartan+L-carnitine groups. In the above-mentioned combination groups, there were nonsignificant decreases in urinary albumin excretion, urinary volume, and more significant decreases in the accumulations of periodic acid schiff, transforming growth factor beta-1 and inducible nitric oxide synthase. Nevertheless, there were no increase in renal tissue antioxidants (superoxide dismutase, glutathione, glutathione peroxidase) and decrease in triglycerides in treatment groups. As a result, our results indicate that AT 1 receptor blockers, when given in combination with antioxidants, enhance their renal protective effects in diabetes mellitus patients in whom oxidative stress plays an important role in the development of organ damage.
Açıklama
Tıpta Uzmanlık Tezi
Anahtar Kelimeler
Anjiyotensin II, Angiotensin II, Diabetes Mellitus-Deneysel, Diabetes Mellitus-Experimental, Diabetik Nefropatiler, Diabetic Nephropathies, Nefroloji, Nephrology
