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

Yıl 2020, Cilt: 45 Sayı: 4, 1653 - 1662, 27.12.2020

Behcet Simsek , Aysun Karabay Bayazıt , Gülfiliz Gönlüşen , Aytül Noyan , Ali Anarat

https://doi.org/10.17826/cumj.781541

Öz

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.

Anahtar Kelimeler

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

Destekleyen Kurum

çukurova üniversitesi tıp fakültesi

Proje Numarası

This study was approved by the Animal Ethics Committee of Cukurova University Affliated to Cukurova University Medical Sciences Experimental Animals Research Center Adana with the verification number “B.30.2.CKO.0.5L.00.00-128”.

Teşekkür

Cukurova University Medical Sciences Experimental Animals Research Center Adana

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

Öz

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.

Anahtar Kelimeler

Ca-dobesilate,, pyelonephritis,, pyelonephritis model,, kidney fibrosis,, renal scar,, renal fibrosis

Proje Numarası

This study was approved by the Animal Ethics Committee of Cukurova University Affliated to Cukurova University Medical Sciences Experimental Animals Research Center Adana with the verification number “B.30.2.CKO.0.5L.00.00-128”.

Kaynakça

• References 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 International Suplements 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, Huang Y, Zhang J, Wang J, Sharma K, Liu Y, Zhao J. Klotho supresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling. J Pathol 2014;234: 4;560–572.
• 5. Strutz F. The role of FGF-2 in renal fibrosis. Frontiers in Bioscience 2009;Suppl 1;125-131.
• 6. Youhua Liu. Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int 2006;69(2):213–217.
• 7. Xu J, Yu T-T, Zhang K, Li M, Shi H-J, Meng X-J, Zhu L-S, Zhu K.. HGF alleviates renal interstitial fibrosis via inhibiting the TGF-β1/SMAD pathway. Eur Rev Med Pharmacol Sci 2018;22 (22):7621-7627.
• 8. Zhou Y, Qi C, Li S, Shao X, Mou S, Ni Z. Diabetic nephropathy can be treated withCalcium Dobesilate by alleviating the chronic inflammatory state and improving endothelial cell function. Cell Physiol Biochem 2018;51:1119-1133.
• 9. Liu X, Liu X. Effect of calcium dobesilate on nephropathy in type 2 diabetic rats. Huazhong Univ Sci Technolog Med Sci 2005;25:36-38.
• 10. Cuaves P. Treatment of basal cell carcinoma with dobesilate. J Am Acad Dermatol 2005;33:526-527.
• 11. 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;20:1230-1236.
• 12. 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;83:1055-1059.
• 13. Palomar R, Mayorga M, Ruiz JC, Cuevas J, Rodrigo E, Cotorruelo JG, Val-Bernal JF, Arias M. Markers of fibrosis in early biopsies of renal transplants. Transplantation Proceedings 2005;37:1468-1470.
• 14. Kehr KK,Leichter HE. Urinary tract infection. In: Clinical Pediatric Nephrology: Kher KK, Makker SP, Eds, 1st Edition, New York: Mc Graw Hill 1992;277-321.
• 15. Simsek B. The prevalence of bacterial strains isolated from urine cultures and their antibiotic susceptibility patterns among children with urinary tract infection. 2019; 1st Euresion Pediatric Congress and VIIth Kosova Pediatric School 17-20 October:OP-06:p48.
• 16. Heptinstall RH. Pyelonephritis: pathological features. In: Pathology of the kidney, Heptinstall RH, Eds. 4th Edition, Boston: Little Brown 1992;1489-1561.
• 17. Rugo HS, O’Hanley P, Bishop AG, Pearce MK, Abrams JS, Howard M, O’Garra A. Local cytokine productionin a murine model of Escherichia Coli pyelonephritis. J Clin Invest 1992;89:1032-1039.
• 18. 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;61:1037-1041.
• 19. Matsumato T, Mitzunoe Y, Ogata N. Antioxidant effect on renal scarring following infection of mannose-sensitive –pilliated bacteria. Nephron 1992;60:210-215.
• 20. Roberts Ja, Kaack MB, Fussell EN. Immunology of pyelonephritis. VII. Effect of allourinol. J Urol 1986;136:960.
• 21. Roberts JA, Roth JK, Dominique G. Immunology of pyelonephritis in the primate model. VI. Effect of complement depletion. J Urol 1983;129:193.
• 22. Shimamura T. Mechanisms of renal tissue destruction in an experimental acute pyelonephritis. Exp Mol Pathol 1981;34:34.
• 23. 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;25:416-426.
• 24. Bottinger EP, Letterio JJ, Roberts AB. Biology of TGF-beta in knockout and transgenic mouse models. Kidney Int 1997;51:1355-1360.