Doksisiklinin 5/6 Renal Ablasyon Nefropatisi ile Gelişen Glomeruloskleroza Etkisi

Amaç: Matriks metalloproteinaz (MMP) inhibitörlerinin böbrek hastalıklarına faydalı etkisi daha önce yayınlanmıştır. Ancak segmental skleroza olan etkileri belirsizdir. Bu çalışmanın amacı bir MMP inhibitörü olan doksisiklinin renal ablasyon nefropatisi ile oluşturulmuş glomerüloskleroza (GS) etkisi ve MMP-2, MMP-9, matriks metalloproteinaz doku inhibitörleri (TIMP)-1, TIMP-2 ve kollajen tip IV ekspresyonlarını incelemektir. Gereç ve Yöntem: Çalışmamızda 32 adet dişi Wistar albino sıçanın 14’üne 5/6 nefrektomi uygulanmış; bunların ve nefrektomi uygulanmayanların yarısına oral doksisiklin verilmiştir (40 mg/kg/gün toplam 28 gün). Sakrifikasyon sonrası histopatolojik olarak glomerüllerdeki sklerotik değişikliklerin yanı sıra, immünfloresans ile MMP-9 düzeyleri ve immünhistokimyasal olarak TIMP-2 ekspresyonu değerlendirilmiştir. Ayrıca enzim bağlı immünosorbent deneyi ile, TIMP-1 ve TIMP-2 düzeyleri; jelatin zimografiyle pro ve aktif MMP-2 ve MMP-9 ölçülmüştür. Bulgular: Araştırma sonucunda 5/6 nefrektomi modelinde doksisiklinin glomerulosklerozu azaltıcı etkisi saptanmış ancak glomerular MMP-9 ya da kortikal pro ve aktif MMP-2 ve pro-MMP9 inhibisyonu görülmemiştir. Tüm gruplarda kortikal dokuda TIMP-1 ve TIMP-2 artışı saptanmıştır. Tip IV kollajen glomerulosklerozun arttığı gruplarda azalmıştır. MMP-9 ekspresyonu ve glomerüloskleroz doksisiklin alan tüm gruplarda azalmıştır. Sonuç: Doksisiklin uygulanması ile renal ablasyon modelinde glomerülosklerozun azaldığını gösterdik, ancak doksisiklinin beklenmedik bir yan etkisi görüldü. Doksisiklinin MMP-2 ve MMP-9 ekspresyonu etkisi glomerulosklerozdaki düzelmeyi açıklayamaz, fakat kortikal TIMP-1 ve TIMP-2’deki yükselme MMP inhibisyonundaki önemli bir faktör olabilir. Diğer MMP ve TIMP tipleri de önemli olabilir. Diğer kollajen tiplerindeki birikim ablasyon nefropatisinde meydana gelen glomerulosklerozda belirgin olabilir.

The Effect of Doxycycline on Glomerulosclerosis in 5/6 Renal Ablation Nephropathy

Objectives: The beneficial effect of matrix metalloproteinases (MMP) inhibitors in renal diseases has been reported. Their effect in segmentalsclerosis is unknown. The aim of this study is to investigate the effect of a MMP inhibitor, doxycycline, onglomeruloscleresis (GS) in renal ablation nephropathy and to evaluate the MMP-2, MMP-9, tissue inhibitors of matrix metalloproteinases (TIMP)-1,TIMP-2, and collagen type IV expressions.Materials and Methods: Fourteen of the 32 female Wistar albinos were 5/6 nephrectomised. Doxycyline was given to half of each group (40 mg/kg/day total 28 days). After sacrification, the GS, MMP-2 and MMP-9 expressions, and TIMP-2 expressions were analyzed histopathologically. Proand active MMP-2 and -9 were analyzed by gelatin zymography. TIMP-1 and TIMP-2 were measured with the enzyme-linked immunoassay.Results: Doxycycline administration to the 5/6 nephrectomy group improved GS but did not inhibit glomerular MMP-9 or cortical pro- and active-MMP-2 and pro-MMP9 but increased TIMP-1 and TIMP-2 expression in all groups in cortical tissue. Type IV collagen was decreased in the groupswhere GS were increased. MMP-9 expression and GS were increased in all groups receiving doxycycline.Conclusion: We have demonstrated improved GS in renal ablation model by doxycycline administration but also doxycycline has an unexpectedadverse effect. The effect of doxycycline on the expression of MMP-2 and -9 cannot explain the improvement in GS but increased cortical TIPM-1and -2 may be an important contributing factor for the inhibition of MMPs. Other types of MMPs and TIMPs may be important. Accumulation ofother types of collagen may be prominent in GS of ablation nephropathy.

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