Laboratuvar Hayvanlarında Deneysel Nefrotoksisite Modelleri

Öz

Hastalıkların mekanizmalarını daha iyi anlamak ve etkili tedavi yöntemleri geliştirebilmek amacıyla in vivo ve in vitro modellerin kullanımı, modern tıbbın ve biyomedikal araştırmaların temel taşlarından biri olarak kabul edilmektedir. Deney hayvanları, bilimsel araştırmalar için vazgeçilmez bir gereklilik olarak karşımıza çıkmakta ve hastalıkların patofizyolojisini anlamada kritik bir rol oynamaktadır. Nefrotoksisite, böbrek dokusunun çeşitli kimyasal maddeler veya ksenobiyotikler tarafından maruz kaldığı zararlı etkileri ifade eder. Bu durum, böbrek hasarına yol açabilecek birçok farklı madde tarafından tetiklenebilir. Örneğin, antibiyotikler (özellikle aminoglikozidler ve vankomisin), non-steroidal antiinflamatuar ilaçlar (NSAID'ler), antiviral ilaçlar, tıbbi görüntülemede kullanılan kontrast maddeler, ağır metaller (kurşun ve cıva) ve kemoterapi ilaçları, böbrek dokusu üzerinde toksik etkiye sahip maddeler arasında yer alır. Böbrekler, bu ilaçlar ve kimyasalların toksik etkilerine karşı oldukça savunmasızdır ve bu savunmasızlık, ciddi böbrek hasarlarına yol açabilir. Ksenobiyotikler, özellikle ilaçlar, akut böbrek hasarı (ABH), kronik böbrek hastalığı (KBH), akut böbrek yetmezliği (ABY) ve son dönem böbrek hastalığı (SDBH) gibi ciddi sağlık sorunlarının önde gelen nedenleri arasındadır. İlaç kaynaklı nefrotoksisite, genellikle üç ana mekanizma üzerinden incelenir: Proksimal tübüler hasar ve akut tübüler nekroz (ATN), kristal formdaki ksenobiyotik veya ilaç metabolitlerinin neden olduğu tübüler tıkanıklık ve ilaçlar ile metabolitlerinin indüklediği interstisyel nefrit. Böbrek fonksiyonlarını gösteren biyokimyasal parametrelerdeki değişiklikler, nefrotoksisitenin tanısında kritik bir rol oynar. Bu derlemede, deneysel nefrotoksisite modelleri, tanısında kullanılan biyobelirteçler ve bu biyobelirteçlerin klinik önemleri ayrıntılı olarak ele alınmıştır.

Anahtar Kelimeler

• Böbrek
• Folik Asit
• Gentamisin
• Hayvanlar
• Laboratuvar

Experimental Nephrotoxicity Models in Laboratory Animals

Öz

The use of in vivo and in vitro models to better understand disease mechanisms and develop effective treatment methods is considered one of the cornerstones of modern medicine and biomedical research. Experimental animals are an indispensable necessity for scientific research, playing a critical role in understanding the pathophysiology of diseases. Nephrotoxicity refers to the harmful effects exerted on kidney tissue by various chemical substances or xenobiotics. This condition can be triggered by a wide range of substances capable of causing kidney damage. For instance, antibiotics (particularly aminoglycosides and vancomycin), non-steroidal anti-inflammatory drugs (NSAIDs), antiviral agents, contrast agents used in medical imaging, heavy metals (such as lead and mercury), and chemotherapeutic drugs are among the substances with toxic effects on kidney tissue. The kidneys are highly vulnerable to the toxic effects of these drugs and chemicals, and this vulnerability can lead to significant kidney damage. Xenobiotics, particularly drugs, are among the leading causes of severe health issues such as acute kidney injury (AKI), chronic kidney disease (CKD), acute renal failure (ARF), and end-stage renal disease (ESRD). Drug-induced nephrotoxicity is generally examined through three main mechanisms: proximal tubular injury and acute tubular necrosis (ATN), tubular obstruction caused by crystal-forming xenobiotics or drug metabolites, and interstitial nephritis induced by drugs and their metabolites. Changes in biochemical parameters reflecting kidney function play a critical role in diagnosing nephrotoxicity. This review provides a detailed examination of experimental nephrotoxicity models, biomarkers used in diagnosis, and the clinical significance of these biomarkers.

Anahtar Kelimeler

• Kidney
• Folic Acid
• Gentamicin
• Animals
• Laboratory
• Nephritis

Kaynakça

1. Allameh, H., Fatemi, I., Malayeri, A. R., Nesari, A., Mehrzadi, S., & Goudarzi, M. (2020). Pretreatment with berberine protects against cisplatin-induced renal injury in male Wistar rats. Naunyn-Schmiedeberg's archives of pharmacology, 393, 1825-1833.
2. Alsharidah M, Abdel-Moneim A-MH, Alsharidah AS, Mobark MA, Rahmani AH, Shata A, Abdellatif AAH, El-Readi MZ, Mohany KM, Al Rugaie O. (2021). Thymoquinone, but Not Metformin, Protects against Gentamicin-Induced Nephrotoxicity and Renal Dysfunction in Rats. Applied Sciences; 11(9):3981.
3. Balakumar, P., Rohilla, A., & Thangathirupathi, A. (2010). Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it?. Pharmacological research, 62(3), 179–186. https://doi.org/10.1016/j.phrs.2010.04.004
4. Besseling, P. J., Pieters, T. T., Nguyen, I. T., de Bree, P. M., Willekes, N., Dijk, A. H., Bovée, D. M., Hoorn, E. J., Rookmaaker, M. B., Gerritsen, K. G., Verhaar, M. C., Gremmels, H. & Joles, J. A. (2021). A plasma creatinine-and urea-based equation to estimate glomerular filtration rate in rats. American Journal of Physiology-Renal Physiology, 320(3), F518-F524.
5. Brans, M., Daminet, S., Mortier, F., Duchateau, L., Lefebvre, H. P., & Paepe, D. (2021). Plasma symmetric dimethylarginine and creatinine concentrations and glomerular filtration rate in cats with normal and decreased renal function. Journal of Veterinary Internal Medicine, 35(1), 303-311.
6. Brilland, B., Boud'hors, C., Wacrenier, S., Blanchard, S., Cayon, J., Blanchet, O., Piccoli, G. B., Henry, N., Djema, A., Coindre, J. P., Jeannin, P., Delneste, Y., Copin, M. C., & Augusto, J. F. (2023). Kidney injury molecule 1 (KIM-1): a potential biomarker of acute kidney injury and tubulointerstitial injury in patients with ANCA-glomerulonephritis. Clinical Kidney Journal, 16(9), 1521–1533. https://doi.org/10.1093/ckj/sfad071
7. Chiou, Y. Y., Jiang, S. T., Ding, Y. S., & Cheng, Y. H. (2020). Kidney-based in vivo model for drug-induced nephrotoxicity testing. Scientific Reports, 10(1), 13640.
8. De Angelis, M. H., Michel, D., Wagner, S., Becker, S., & Beckers, J. (2007). Chemical mutagenesis in mice. In The mouse in biomedical research (pp. 225-260). Academic Press.

9. Delaney, M. A., Kowalewska, J., & Treuting, P. M. (2018). Urinary system. In Comparative Anatomy and Histology (pp. 275-301). Academic Press.
10. Dipiro, J. T., Talbert, R. L., Yee, G. C., Matzke, G. R., Wells, B. G., & Posey, L. M. (2014). Pharmacotherapy: a pathophysiologic approach, ed. Connecticut: Appleton and Lange, 4, 141-142.
11. Doyle, A., McGarry, M. P., Lee, N. A., & Lee, J. J. (2012). The construction of transgenic and gene knockout/knockin mouse models of human disease. Transgenic Research, 21(2), 327–349. https://doi.org/10.1007/s11248-011-9537-3
12. Erseckin, V., Mert, H., İrak, K., Yildirim, S., & Mert, N. (2022). Nephroprotective effect of ferulic acid on gentamicin-induced nephrotoxicity in female rats. Drug and Chemical Toxicology, 45(2), 663-669.
13. Fernando, S., & Polkinghorne, K. R. (2020). Cystatin C: not just a marker of kidney function. Brazilian Journal of Nephrology, 42, 6-7.
14. Goossens, J. F., Thuru, X., & Bailly, C. (2021). Properties and reactivity of the folic acid and folate photoproduct 6-formylpterin. Free Radical Biology & Medicine, 171, 1–10. https://doi.org/10.1016/j.freeradbiomed.2021.05.002
15. Hassan, O. Y., Khatal, A. A., Alagouri, I. I., Eljrieby, L. R., Aljaghdaf, H. M., & Muftah, S. S. (2023). Study of the Histological and Histopathological Effects of Garlic Extract (Allium sativum) on Cisplatin-Induced Kidney Damage in Rabbits. Journal of Advances in Medicine and Medical Research, 35(22), 134-152.
16. Hau, J. (2008). Animal Models for Human Diseases. In: Conn, P.M. (eds) Sourcebook of Models for Biomedical Research. Humana Press.
17. Huang, H., Jin, W. W., Huang, M., Ji, H., Capen, D. E., Xia, Y., Yuan, J., Păunescu, T. G. & Lu, H. A. J. (2020). Gentamicin-induced acute kidney injury in an animal model involves programmed necrosis of the collecting duct. Journal of the American Society of Nephrology: JASN, 31(9), 2097.
18. Kang S, Chen T, Hao Z, Yang X, Wang M, Zhang Z, Hao S, Lang F, Hao H. (2022). Oxymatrine Alleviates Gentamicin-Induced Renal Injury in Rats. Molecules, 27(19):6209. https://doi.org/10.3390/molecules27196209
19. Karadeniz, A., Yildirim, A., Simsek, N., Kalkan, Y., & Celebi, F. (2008). Spirulina platensis protects against gentamicin-induced nephrotoxicity in rats. Phytotherapy research: PTR, 22(11), 1506–1510. https://doi.org/10.1002/ptr.2522
20. Kashani, K., Rosner, M. H., & Ostermann, M. (2020). Creatinine: From physiology to clinical application. European journal of internal medicine, 72, 9-14.
21. Kaya, M. & Çevik, A. (2011). Hayvan deneylerinde planlanma ve model seçimi. Deneysel Tıp Araştırma Enstitüsü Dergisi, 1 (2), 36-39. Retrieved from https://dergipark.org.tr/en/pub/iudtaed/issue/8971/111908
22. Khorramizadeh, M. R., & Saadat, F. (2020). Animal models for human disease. In Animal Biotechnology (pp. 153-171). Academic Press.
23. Khusainova, M. A. (2023). Cystatin C is an early marker of decreased kidney function. Oriental renaissance: Innovative, educational, natural and social sciences, 3(1), 485-490.
24. Kim, Y. D., Yim, D. H., Eom, S. Y., Moon, S. I., Park, C. H., Kim, G. B., Yu, S. D., Choi, B. S., Park, J. D., & Kim, H. (2015). Temporal changes in urinary levels of cadmium, N-acetyl-β-d-glucosaminidase and β2-microglobulin in individuals in a cadmium-contaminated area. Environmental toxicology and pharmacology, 39(1), 35–41. https://doi.org/10.1016/j.etap.2014.10.016
25. Le, X., & Hanna, E. Y. (2018). Optimal regimen of cisplatin in squamous cell carcinoma of head and neck yet to be determined. Annals of translational medicine, 6(11), 229.
26. Lee, M. C., Cheng, K. J., Chen, S. M., Li, Y. C., Imai, K., Lee, C. M., & Lee, J. A. (2019). A novel preventive mechanism of gentamicin‐induced nephrotoxicity by atorvastatin. Biomedical Chromatography, 33(11), e4639.
27. Lee, M., Hong, N., Lee, Y. H., Kang, E. S., Cha, B. S., & Lee, B. W. (2018). Elevated N-acetyl-β-d-glucosaminidase, a urinary tubular damage marker, is a significant predictor of carotid artery atherosclerosis in type 1 diabetes, independent of albuminuria: A cross-sectional study. Journal of diabetes and its complications, 32(8), 777–783. https://doi.org/10.1016/j.jdiacomp.2018.05.019
28. Li, D., Li, B., Rui, Y., Xie, H., Zhang, X., Liu, R., & Zeng, N. (2022). Piperazine ferulate attenuates gentamicin-induced acute kidney injury via the NF-κB/NLRP3 pathway. Phytomedicine, 99, 154021.
29. Li, Q. X., Jiang, X. Y., Wang, X., & Li, J. (2021). Protective Effects of Valsartan on Gentamicin Induced Tubular Injury through Down Regulation of Urinary N-Acetyl-Β-D-Glucosaminidase in Rats. Indian Journal of Pharmaceutical Sciences, 83(1).
30. Liangos, O., Perianayagam, M. C., Vaidya, V. S., Han, W. K., Wald, R., Tighiouart, H., MacKinnon, R. W., Li, L., Balakrishnan, V. S., Pereira, B. J., Bonventre, J. V., & Jaber, B. L. (2007). Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. Journal of the American Society of Nephrology: JASN, 18(3), 904–912. https://doi.org/10.1681/ASN.2006030221.
31. Liu, Q., Zong, R., Li, H., Yin, X., Fu, M., Yao, L., Sun, J. & Yang, F. (2021). Distribution of urinary N‐acetyl‐beta‐D‐glucosaminidase and the establishment of reference intervals in healthy adults. Journal of Clinical Laboratory Analysis, 35(5), e23748.
32. Maurer, K. J., & Quimby, F. W. (2015). Animal models in biomedical research. In Laboratory animal medicine (pp. 1497-1534). Academic Press.
33. McSweeney, K. R., Gadanec, L. K., Qaradakhi, T., Ali, B. A., Zulli, A., & Apostolopoulos, V. (2021). Mechanisms of cisplatin-induced acute kidney injury: pathological mechanisms, pharmacological interventions, and genetic mitigations. Cancers, 13(7), 1572.
34. Mohammed-Ali, Z., Carlisle, R. E., Nademi, S., & Dickhout, J. G. (2017). Animal models of kidney disease. In Animal Models for the Study of Human Disease (pp. 379-417). Academic Press.
35. Nikolic, T., Petrovic, D., Matic, S., Turnic, T. N., Jeremic, J., Radonjic, K., Srejovic, I., Zivkovic, V., Bolevich, S., Bolevich, S. & Jakovljevic, V. (2020). The influence of folic acid-induced acute kidney injury on cardiac function and redox status in rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 393, 99-109.
36. Onopiuk, A., Tokarzewicz, A., & Gorodkiewicz, E. (2015). Cystatin C: a kidney function biomarker. Advances in clinical chemistry, 68, 57-69.
37. Park, H. C., Hwang, J. H., Kang, A. Y., Ro, H., Kim, M. G., An, J. N., In Park, J., Kim, S. H., Yang, J., Oh, Y. K., Oh, K. H., Noh, J. W., Cheong, H. I., Hwang, Y. H., & Ahn, C. (2012). Urinary N-acetyl-β-D glucosaminidase as a surrogate marker for renal function in autosomal dominant polycystic kidney disease: 1 year prospective cohort study. BMC nephrology, 13, 93. https://doi.org/10.1186/1471-2369-13-93
38. Ramar, M., Ravi, S., Duraisamy, P., Krishnan, M., Martin, L. C., Kumaresan, M., Munusamy, A. & Manikandan, B. (2023). Gentamicin-induced acute nephrotoxicity counteraction using Boerhaavia diffusa in Swiss albino mice. Comparative Clinical Pathology, 1-13.
39. Randjelovic, P., Veljkovic, S., Stojiljkovic, N., Sokolovic, D., & Ilic, I. (2017). Gentamicin nephrotoxicity in animals: Current knowledge and future perspectives. EXCLI journal, 16, 388.
40. Schley, G., Köberle, C., Manuilova, E., Rutz, S., Forster, C., Weyand, M., Formentini, I., Klentsch-Engel, R., Eckardt, K., & Willam, C. (2015). Comparison of plasma and urine biomarker performance in acute kidney injury. PloS one, 10(12), e0145042.
41. Sluman, C., Gudka, P. M., & McCormick, K. (2020). Acute Kidney Injury: Pre-renal, Intra-renal and Post-renal. Renal Medicine and Clinical Pharmacy, 23-44.
42. Stallons, L. J., Whitaker, R. M., & Schnellmann, R. G. (2014). Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis. Toxicology letters, 224(3), 326-332.
43. Suliska, N., Kurniati, N. F., & Sukandar, E. Y. (2021). Anredera cordifolia (Ten.) Steenis and Sonchus arvensis L. İnhibit gentamicin-induced nephrotoxicity: The role of urinary N-acetyl beta-D-glucosaminidase. Journal of Reports in Pharmaceutical Sciences, 10(2), 256-260.
44. Tanaka, S. I., Fujioka, Y., Tsujino, T., Ishida, T., & Hirata, K. I. (2022). Association between urinary N-acetyl-β-glucosaminidase activity–urinary creatinine concentration ratio and risk of disability and all-cause mortality. Plos one, 17(3), e0265637.
45. Togashi, Y., Sakaguchi, Y., Miyamoto, M., & Miyamoto, Y. (2012). Urinary cystatin C as a biomarker for acute kidney injury and its immunohistochemical localization in kidney in the CDDP-treated rats. Experimental and toxicologic pathology, 64(7-8), 797-805.
46. Treacy, O., Brown, N. N., & Dimeski, G. (2019). Biochemical evaluation of kidney disease. Translational andrology and urology, 8(Suppl 2), S214.
47. Vaidya, V. S., Ozer, J. S., Dieterle, F., Collings, F. B., Ramirez, V., Troth, S., Muniappa, N., Thudium, D., Gerhold, D., Holder, D. J., Bobadilla, N. A., Marrer, E., Perentes, E., Cordier, A., Vonderscher, J., Maurer, G., Goering, P. L., Sistare, F. D., & Bonventre, J. V. (2010). Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nature biotechnology, 28(5), 478–485. https://doi.org/10.1038/nbt.1623
48. Werner, M., Costa, M. J., Mitchell, L. G., & Nayar, R. (1995). Nephrotoxicity of xenobiotics. Clinica Chimica Acta, 237(1-2), 107-154.
49. Wu, H., & Huang, J. (2018). Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies. Current drug metabolism, 19(7), 559-567.
50. Yan, L. J. (2021). Folic acid‐induced animal model of kidney disease. Animal models and experimental medicine, 4(4), 329-342.
51. Yerramilli, M., Farace, G., Quinn, J., & Yerramilli, M. (2016). Kidney Disease and the Nexus of Chronic Kidney Disease and Acute Kidney Injury: The Role of Novel Biomarkers as Early and Accurate Diagnostics. The Veterinary clinics of North America. Small animal practice, 46(6), 961–993. https://doi.org/10.1016/j.cvsm.2016.06.011.
52. Yin, C., & Wang, N. (2016). Kidney injury molecule-1 in kidney disease. Renal failure, 38(10), 1567-1573.
53. Zaaba, N. E., Beegam, S., Elzaki, O., Yasin, J., Nemmar, B. M., Ali, B. H., Adeghate, E., & Nemmar, A. (2022). The Nephroprotective Effects of α-Bisabolol in Cisplatin-Induced Acute Kidney Injury in Mice. Biomedicines, 10(4),842. https://doi.org/10.3390/biomedicines10040842.
54. Zhang, W., Yang, Y., Gao, H., Zhang, Y., Jia, Z., & Huang, S. (2019). Inhibition of mitochondrial complex i aggravates folic acid-induced acute kidney injury. Kidney and Blood Pressure Research, 44(5), 1002-1013.