Behcet SİMSEK, Aysun Karabay BAYAZIT, Gülfiliz GÖNLÜŞEN, Aytül NOYAN, Ali ANARAT

Deneysel piyelonefrit modelinde Ca-Dobesilate'in renal skar oluşumuna etkisi

Amaç: Bu çalışma, venöz yetmezlikte yaygın kullanımda olan kalsiyum dobesilatın, sıçan piyelonefrit modelinde renal skar ve transforming büyüme faktörü beta1 (TGFb1), temel fibroblast büyüme faktörü (bFGF) ve hepatosit büyüme faktörü-beta (HGF-beta) dokudaki düzeylerini değerlendirmeyi amaçlamıştır. Gereç ve Yöntem: Böbreğe E Coli (ATCC 25922) enjeksiyonunu takiben; tedavisiz- siprofloksasin alan – siprofloksasin ve kalsiyum dobesilat uygulanan olmak üzere her biri 7 sıçandan oluşan gruplar oluşturuldu. Tedavi almayan sıçan grupları bakteri ekimini takiben; sırası ile 24 ve 72 saat sonra ve 14 ve 28 gün sonra sonlandırıldı. Tedavi alan gruplardaki sıçanlar ise 14 ve 28 gün sonra sonlandırıldılar. Piyelonefrit ve fibrosis tanıları, TGFb, bFGF, HGF-beta semikantitatif olarak immünhistokimya boyama ile skorlandı. Bulgular: Bakteriyel inokulasyondan 14 gün sonra sonuçlandırılan gruplar içinde; siprofloksasin ve kalsiyum dobesilat birlikte uygulanan sıçanlarda sadece siprofloksasin alan ve hiç tedavi almayan sıçanlara göre piyelonefrit ve fibrosis yayılımı daha düşük idi. Ancak, kalsiyum dobesilatın piyelonefrit ve fibrosis skorları üzerine etkisinin tedavi kesildikten sonra devam etmediği görüldü. Sonuç: Kalsiyum dobesilat, doza ve tedavi süresine bağlı olarak pyelonefrit ve renal skar şiddetini azaltabilir. Tedavi doz ve süresinin belirlenebilmesi için ileri çalışmalara ihtiyaç vardır.

The effect of Ca-Dobesilate over renal scar formation in an experimental pyelonephritis model

Purpose: This study was conducted to evaluate the effects of the drug: Ca-Dobesilate (CaD) which has been in common use in venous insufficiency treatment; on renal scarring and expressions of transforming growth factor beta1 (TGFb1), basic fibroblast growth factor (bFGF) and hepatocyte growth factor-beta (HGF-beta) in a rat pyelonephritis model. Materialw and Methods: Eight pyelonephritis groups, each constituting of 7 rats were developed as no treatment - ciprofloxacin – ciprofloxacin and CaD administered groups; following injecting E Coli (ATCC 25922) into kidney. No treatment given rat groups were sacrificed following 24h, 72 h, 14d and 28d from bacterial seeding respectively. Rats from treatment groups were sacrificed after 14d and 28d accordingly. Diagnoses of pyelonephritis and fibrosis, TGFb, bFGF and HGF-beta were scored semiquantitatively by immunohistochemical staining. Results: The extent of pyelonephritis and fibrosis was lower in rats treated with ciprofloxacin and CaD compared to sole ciprofloxacin and no treatment administered counterparts among groups terminated after 2wks following bacterial inoculation. However, CaD effect on pyelonephritis and fibrosis scores did not persist after treatment was discontinued. Conclusion: CaD might alleviate pyelonephritis and scarring, depending on dosage and treatment period and further studies are needed to determine optimum treatment dose and duration.

Keywords:

ca-dobesilate, kidney fibrosis, pyelonephritis model, pyelonephritis, ,

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1. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol. 2000;15:290-301.
2. Eddy AA. Overview of the cellular and molecular basis kidney fibrosis. Kidney Int Suppl (2011). 2014;4:2-8.
3. Genovese F, Manresa AA, Leeming DJ, Karsdal MA, Boor P. The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis? Fibrogenesis Tissue Repair. 2014;7:4.
4. Guan X, Nie L, He T, Yang K, Xiao T, Wang S et al. Klotho supresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling. J Pathol. 2014;234:560–72.
5. Strutz F. The role of FGF -2 in renal fibrosis. Front Biosci. 2009;(Suppl 1):125-31.
6. Youhua Liu. Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int. 2006;69:213–17.
7. Xu J, Yu T-T, Zhang K, Li M, Shi H -J, Meng X-J et al. HGF alleviates renal interstitial fibrosis via inhibiting the TGF-β1/SMAD pathway. Eur Rev Med Pharmacol Sci. 2018;22:7621-7.
8. Zhou Y, Qi C, Li S, Shao X, Mou S, Ni Z. Diabetic nephropathy can be treated with Calcium Dobesilate by alleviating the chronic inflammatory state and improving endothelial cell function. Cell Physiol Biochem. 2018;51:1119-33.
9. Liu X, Liu X. Effect of calcium dobesilate on nephropathy in type 2 diabetic rats. Huazhong Univ Sci Technolog Med Sci. 2005;25:36-8.
10. Cuaves P. Treatment of basal cell carcinoma with dobesilate. J Am Acad Dermatol. 2005;33:526-7.
11. World Medical Association Declaration of Helsinki. Adopted by the 18th World Medical Assembly, Helsinki 1964 as amended by the 64th World Medical Assembly, Fortaleza, Brazil, October 2013.
12. Bıyıklı NK, Tuğtepe H, Çakalağaoğlu F, İlki A Alpay H. Downregulation of the expression of bone morphogenic protein 7 in experimental pyelonephritis. Pediatr Nephrol. 2005;20:1230-6.
13. Kavukçu S, Soylu A, Türkmen M, Sarıoğlu S, Büyükgebiz B, Güre A. The role of vitamin A in preventing renal scarring secondary to pyelonephritis. BJU Int. 1999;83:1055-9.
14. Palomar R, Mayorga M, Ruiz JC, Cuevas J, Rodrigo E, Cotorruelo JG et al. Markers of fibrosis in early biopsies of renal transplants. Transplant Proc. 2005;37:1468-70.
15. Kehr KK, Leichter HE. Urinary tract infection. In Clinical Pediatric Nephrology (Eds Kher KK, Makker SP): 1st Ed., New York: Mc Graw Hill. 1992;277-321.
16. Simsek B. The prevalence of bacterial strains isolated from urine cultures and their antibiotic susceptibility patterns among children with urinary tract infection. 1st Euresion Pediatric Congress and VIIth Kosova Pediatric School Abstract Book,17-20 October 2019, Kosova, OP-06, p.48.
17. Heptinstall RH (editor). Pyelonephritis: pathological features. In Pathology of The Kidney. 4th ed., Boston: Little Brown, 1992;1489-561.
18. Rugo HS, O’Hanley P, Bishop AG, Pearce MK, Abrams JS, Howard M et al. Local cytokine productionin a murine model of Escherichia Coli pyelonephritis. J Clin Invest. 1992;89:1032-9.
19. Yağmurlu A, Boleken ME, Ertoy D, Özsan M, Gökçora IH, Dindar H. Preventive effect of pentoxyfilline on renal scarring in rat model of pyelonephritis. Urology. 2003;61:1037-41.
20. Matsumato T, Mitzunoe Y, Ogata N. Antioxidant effect on renal scarring following infection of mannose-sensitive –pilliated bacteria. Nephron. 1992;60:210-5.
21. Roberts Ja, Kaack MB, Fussell EN. Immunology of pyelonephritis. VII. Effect of allourinol. J Urol. 1986;136:960.
22. Roberts JA, Roth JK, Dominique G. Immunology of pyelonephritis in the primate model. VI. Effect of complement depletion. J Urol. 1983;129:193.
23. Shimamura T. Mechanisms of renal tissue destruction in an experimental acute pyelonephritis. Exp Mol Pathol. 1981;34:34.
24. Unal Y, Tuncal S, Kosmaz K, Kucuk B, Kımet K, Cavusoglu T. The effect of Calcium Dobesilate on liver damage in experimental obstructive jaundice. J Invest Surg. 2019;32:238-44.
25. Li X, Bu X, Yan F, Wang F, Wei D, Yuan J et al. Deletion of discoidin domain receptor 2 attenuates renal interstitial fibrosis in a murine unilateral ureteral obstruction model. Ren Fail. 2019;41:481-8.
26. Wang Y, Zuo B, Wang N, Li S, Liu C, Sun D. Calcium dobesilate mediates renal interstitial fibrosis and delay renal capillary loss through Sirt1/p53 signaling pathway. Biomed Pharmacother. 2020;132:110798.
27. Zhou Y, Qi C, Shao X,Mou S, Ni Z. Diabetic nephropathy can be treated with Calcium Dobesilate by alleviating the chronic inflammatory state and improving endothelial cell function. Cell Physiol Biochem. 2018;51:1119-33.
28. Dong J, Liu X, Liu S, Li M, Xu Y, Cui B. Effects of calcium dobesilate on glomerulusTIMP1 and collagen IV of Diabetic rats. Huazhong Univ Sci Technolog Med Sci 2005;25:416-26.
29. Bottinger EP, Letterio JJ, Roberts AB. Biology of TGF-beta in knockout and transgenic mouse models. Kidney Int. 1997;51:1355-60.