Protective effects of insulin-like growth factor (IGF-1) in doxorubicin-induced experimental liver and kidney injury
Öz
Purpose: This study aimed to investigate the protective effects of insulin-like growth factor-1 (IGF-1) against doxorubicin (DOX)-induced liver and kidney damage in rats using biochemical, immunohistochemical, and histopathological methods.
Materials and Methods: A total of 32 Wistar albino rats were randomly assigned into four groups: Control, DOX (4 mg/kg/week), IGF-1 (1 µg/kg daily), and DOX + IGF-1 (DOX 4 mg/kg/week + IGF-1 1 µg/kg daily). After the four-week experimental protocol, blood, liver, and kidney tissues were collected under anesthesia. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), urea, and creatinine were analyzed biochemically. Total antioxidant status (TAS) and total oxidant status (TOS) in liver and kidney tissues were measured using ELISA. Gene expression levels of HIF-1α and iNOS were evaluated by real-time PCR. Histopathological and immunohistochemical (Caspase-3, TNF-α, and FGF-2) evaluations were conducted on liver and kidney tissues.
Results: DOX significantly increased serum ALT, AST, BUN, urea, and creatinine levels and elevated TOS while reducing TAS in tissues). HIF-1α expression was markedly upregulated (+5.50-fold), indicating oxidative damage. IGF-1 administration reduced serum ALT, AST, BUN, urea, and creatinine levels, increased TAS, and decreased TOS. Expression levels of HIF-1α and iNOS approached those of the control group. DOX caused significant histopathological damage and increased Caspase-3 and TNF-α expressions in the liver and Caspase-3 and FGF-2 expressions in the kidney. These alterations were ameliorated by IGF-1 treatment.
Conclusion: The findings suggest that IGF-1 exerts protective effects against DOX-induced hepatorenal toxicity, possibly through its antioxidant, anti-inflammatory, and anti-apoptotic properties.
Anahtar Kelimeler
Doxorubusin Oxidative Damage IGF-1 hepatotoxicity nephrotoxicity
Etik Beyan
Ethics committee approval was received from Pamukkale University Animal Experiments Ethics Committee on 12.05.2022 (Protocol no. PAUHDEK-2021/06). All experimental procedures were carried out in accordance with Laboratory Animal Care and Use.
Destekleyen Kurum
Pamukkale University Scientific Research Projects Coordination
Proje Numarası
2022SABE013.
Kaynakça
- Simmons A, Vacek JL, Meyers D. Anthracycline-induced cardiomyopathy. Postgrad Med. 2008;120:67–72.
- Tektemur A, Tektemur NK, Güzel EE. The therapeutic effect of hesperetin on doxorubicin-induced testicular toxicity: potential roles of the mechanistic target of rapamycin kinase (mTOR) and dynamin-related protein 1 (DRP1). Toxicol Appl Pharmacol. 2022;435:115833.
- Patil L, Balaraman R. Effect of green tea extract on doxorubicin-induced cardiovascular abnormalities: antioxidant action. Iran J Pharm Res. 2011;10(1):89.
- Renu K, Pureti LP, Vellingiri B, Valsala Gopalakrishnan A. Toxic effects and molecular mechanism of doxorubicin on different organs–an update. Toxin Rev. 2022;41:650–74.
- Alkuraishy HM, Al-Gareeb AI, Al-Hussaniy HA. Doxorubicin-induced cardiotoxicity: molecular mechanism and protection by conventional drugs and natural products. Int J Clin Oncol Cancer Res. 2017;2:31–44.
- Jungsuwadee P. Doxorubicin-induced cardiomyopathy: an update beyond oxidative stress and myocardial cell death. Cardiovasc Regen Med. 2016;3:1127.
- Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, Songur A. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res. 2007;38:380–85.
- Nagai K, Fukuno S, Oda A, Konishi H. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs. 2016;27:17–23.
- Kasprzak A. Autophagy and the insulin-like growth factor (IGF) system in colonic cells: implications for colorectal neoplasia. Int J Mol Sci. 2023;24:3665.
- Pang Y, Zheng B, Fan LW, Rhodes PG, Cai Z. IGF-1 protects oligodendrocyte progenitors against TNFα-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway. Glia. 2007;55:1099–1107.
- Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P et al. Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol A Biol Sci Med Sci. 2012;67:313–29.
- Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52–79.
- Peter S, Alven S, Maseko RB, Aderibigbe BA. Doxorubicin-based hybrid compounds as potential anticancer agents. Molecules. 2022;27:4478.
- Chen X, Zhang Y, Zhu Z, Liu H, Guo H, Xiong C et al. Protective effect of berberine on doxorubicin‑induced acute hepatorenal toxicity in rats. Mol Med Rep. 2016;13:3953–60.
- Aljobaily N, Viereckl MJ, Hydock DS, Aljobaily H, Wu TY, Busekrus R et al. Creatine alleviates doxorubicin-induced liver damage by inhibiting liver fibrosis, inflammation, oxidative stress, and cellular senescence. Nutrients. 2020;13:41.
- AlAsmari AF, Ali N, Alharbi M, Alqahtani F, Alasmari F, Almoqbel D et al. Geraniol ameliorates doxorubicin-mediated kidney injury through alteration of antioxidant status, inflammation, and apoptosis: potential roles of NF-κB and Nrf2/HO-1. Nutrients. 2022;14:1620.
- King S, Mohiuddin JJ, Dekaney CM. Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage. Am J Physiol Gastrointest Liver Physiol. 2013;305:151–62.
- Dik B, Er A, Çorum O. Determination of protective effectiveness of Nerium oleander distillation in doxorubicin-induced organ damages. Eurasian J Vet Sci. 2014;30:63–7.
- Varela-López A, Battino M, Navarro-Hortal MD, Giampieri F, Forbes-Hernández TY, Romero-Márquez JM et al. An update on the mechanisms related to cell death and toxicity of doxorubicin and the protective role of nutrients. Food Chem Toxicol. 2019;134:110834.
- Simůnek T, Stérba M, Popelová O, Adamcová M, Hrdina R, Gersl V et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep. 2009;61:154–71.
- Wheaton WW, Chandel NS. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol. 2011;300:385–93.
- Nanayakkara G, Alasmari A, Mouli S, Eldoumani H, Quindry J, McGinnis G et al. Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;309:867–79.
- El-Moselhy MA, El-Sheikh AAK. Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity. Biomed Pharmacother. 2014;68:101–10.
- Rashid S, Ali N, Nafees S, Ahmad ST, Arjumand W, Hasan SK et al. Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats. Hum Exp Toxicol. 2013;32:337–45.
- Kuzu M, Yıldırım S, Kandemir FM, Küçükler S, Çağlayan C, Türk E et al. Protective effect of morin on doxorubicin-induced hepatorenal toxicity in rats. Chem Biol Interact. 2019; 308:89–100.
- Yildirim N, Lale A, Yazıcı GN, Sunar M, Aktas M, Ozcicek A et al. Ameliorative effects of Liv-52 on doxorubicin-induced oxidative damage in rat liver. Biotech Histochem. 2022;97:616–21.
- Refaie MMM, Âmin EF, El-Tahawy NF, Abdelrahman AM. Possible protective effect of diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol. 2016;9507563.
- Mattison PC, Soler-García AA, Das JR, Jerebtsova M, Perazzo S, Tang P et al. Role of circulating fibroblast growth factor-2 in lipopolysaccharide-induced acute kidney injury in mice. Pediatr Nephrol. 2012;27:469–83.
- Yücel E, Zengin MN, Özmen Ö, Çiftçi O. Doksorubusin kaynaklı kardiyotoksisite modelinde insülin benzeri büyüme faktörünün (igf-1) etkisinin araştırılması. Osmangazi Tıp Dergisi. 2024;46:945-54.
Doksorubisin ile oluşturulan deneysel karaciğer ve böbrek hasarında insülin benzeri büyüme faktörünün (IGF-1) iyileştirici etkilerinin araştırılması
Öz
Amaç: Bu çalışmanın amacı, biyokimyasal, immünohistokimyasal ve histopatolojik yöntemler kullanılarak sıçanlarda doksorubisin (DOX) kaynaklı karaciğer ve böbrek hasarına karşı insülin benzeri büyüme faktörü-1'in (IGF-1) koruyucu etkilerinin araştırılmasıdır.
Gereç ve Yöntem: Toplam 32 Wistar albino sıçanı rastgele dört gruba ayrıldı: Kontrol, DOX (4 mg/kg/hafta), IGF-1 (günlük 1 µg/kg) ve DOX + IGF-1 (DOX 4 mg/kg/hafta + IGF-1 1 µg/kg günlük). Dört haftalık deneysel protokolden sonra, anestezi altında kan, karaciğer ve böbrek dokuları toplandı. Alanin aminotransferaz (ALT), aspartat aminotransferaz (AST), kan üre azotu (BUN), üre ve kreatinin serum seviyeleri biyokimyasal olarak analiz edildi. Karaciğer ve böbrek dokularındaki toplam antioksidan durum (TAS) ve toplam oksidan durum (TOS) ELISA kullanılarak ölçüldü. HIF-1α ve iNOS gen ekspresyon seviyeleri gerçek zamanlı PCR ile değerlendirildi. Karaciğer ve böbrek dokularında histopatolojik ve immünohistokimyasal (Kaspaz-3, TNF-α ve FGF-2) değerlendirmeler yapıldı.
Bulgular: DOX, serum ALT, AST, BUN, üre ve kreatinin seviyelerini önemli ölçüde artırdı ve dokularda TAS'ı azaltırken TOS'u yükseltti. HIF-1α ekspresyonu belirgin şekilde yukarı düzenlendi (+5,50 kat), bu da oksidatif hasarı gösteriyordu. IGF-1 uygulaması serum ALT, AST, BUN, üre ve kreatinin seviyelerini düşürdü, TAS'ı artırdı ve TOS'u azalttı. HIF-1α ve iNOS ekspresyon seviyeleri kontrol grubundakilere yaklaştı. DOX, karaciğerde önemli histopatolojik hasara ve artan Kaspaz-3 ve TNF-α ifadelerine ve böbrekte Kaspaz-3 ve FGF-2 ifadelerine neden oldu. Bu değişiklikler IGF-1 tedavisiyle iyileştirildi.
Sonuç: Bulgular, IGF-1'in muhtemelen antioksidan, anti-inflamatuar ve anti-apoptotik özellikleri yoluyla DOX kaynaklı hepatorenal toksisiteye karşı koruyucu etkiler uyguladığını göstermektedir.
Anahtar Kelimeler
Doksorubusin Hepatotoksite IGF-1 Oksidatif Hasar Nefrotoksisite
Proje Numarası
2022SABE013.
Kaynakça
- Simmons A, Vacek JL, Meyers D. Anthracycline-induced cardiomyopathy. Postgrad Med. 2008;120:67–72.
- Tektemur A, Tektemur NK, Güzel EE. The therapeutic effect of hesperetin on doxorubicin-induced testicular toxicity: potential roles of the mechanistic target of rapamycin kinase (mTOR) and dynamin-related protein 1 (DRP1). Toxicol Appl Pharmacol. 2022;435:115833.
- Patil L, Balaraman R. Effect of green tea extract on doxorubicin-induced cardiovascular abnormalities: antioxidant action. Iran J Pharm Res. 2011;10(1):89.
- Renu K, Pureti LP, Vellingiri B, Valsala Gopalakrishnan A. Toxic effects and molecular mechanism of doxorubicin on different organs–an update. Toxin Rev. 2022;41:650–74.
- Alkuraishy HM, Al-Gareeb AI, Al-Hussaniy HA. Doxorubicin-induced cardiotoxicity: molecular mechanism and protection by conventional drugs and natural products. Int J Clin Oncol Cancer Res. 2017;2:31–44.
- Jungsuwadee P. Doxorubicin-induced cardiomyopathy: an update beyond oxidative stress and myocardial cell death. Cardiovasc Regen Med. 2016;3:1127.
- Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, Songur A. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res. 2007;38:380–85.
- Nagai K, Fukuno S, Oda A, Konishi H. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs. 2016;27:17–23.
- Kasprzak A. Autophagy and the insulin-like growth factor (IGF) system in colonic cells: implications for colorectal neoplasia. Int J Mol Sci. 2023;24:3665.
- Pang Y, Zheng B, Fan LW, Rhodes PG, Cai Z. IGF-1 protects oligodendrocyte progenitors against TNFα-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway. Glia. 2007;55:1099–1107.
- Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P et al. Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol A Biol Sci Med Sci. 2012;67:313–29.
- Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52–79.
- Peter S, Alven S, Maseko RB, Aderibigbe BA. Doxorubicin-based hybrid compounds as potential anticancer agents. Molecules. 2022;27:4478.
- Chen X, Zhang Y, Zhu Z, Liu H, Guo H, Xiong C et al. Protective effect of berberine on doxorubicin‑induced acute hepatorenal toxicity in rats. Mol Med Rep. 2016;13:3953–60.
- Aljobaily N, Viereckl MJ, Hydock DS, Aljobaily H, Wu TY, Busekrus R et al. Creatine alleviates doxorubicin-induced liver damage by inhibiting liver fibrosis, inflammation, oxidative stress, and cellular senescence. Nutrients. 2020;13:41.
- AlAsmari AF, Ali N, Alharbi M, Alqahtani F, Alasmari F, Almoqbel D et al. Geraniol ameliorates doxorubicin-mediated kidney injury through alteration of antioxidant status, inflammation, and apoptosis: potential roles of NF-κB and Nrf2/HO-1. Nutrients. 2022;14:1620.
- King S, Mohiuddin JJ, Dekaney CM. Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage. Am J Physiol Gastrointest Liver Physiol. 2013;305:151–62.
- Dik B, Er A, Çorum O. Determination of protective effectiveness of Nerium oleander distillation in doxorubicin-induced organ damages. Eurasian J Vet Sci. 2014;30:63–7.
- Varela-López A, Battino M, Navarro-Hortal MD, Giampieri F, Forbes-Hernández TY, Romero-Márquez JM et al. An update on the mechanisms related to cell death and toxicity of doxorubicin and the protective role of nutrients. Food Chem Toxicol. 2019;134:110834.
- Simůnek T, Stérba M, Popelová O, Adamcová M, Hrdina R, Gersl V et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep. 2009;61:154–71.
- Wheaton WW, Chandel NS. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol. 2011;300:385–93.
- Nanayakkara G, Alasmari A, Mouli S, Eldoumani H, Quindry J, McGinnis G et al. Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;309:867–79.
- El-Moselhy MA, El-Sheikh AAK. Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity. Biomed Pharmacother. 2014;68:101–10.
- Rashid S, Ali N, Nafees S, Ahmad ST, Arjumand W, Hasan SK et al. Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats. Hum Exp Toxicol. 2013;32:337–45.
- Kuzu M, Yıldırım S, Kandemir FM, Küçükler S, Çağlayan C, Türk E et al. Protective effect of morin on doxorubicin-induced hepatorenal toxicity in rats. Chem Biol Interact. 2019; 308:89–100.
- Yildirim N, Lale A, Yazıcı GN, Sunar M, Aktas M, Ozcicek A et al. Ameliorative effects of Liv-52 on doxorubicin-induced oxidative damage in rat liver. Biotech Histochem. 2022;97:616–21.
- Refaie MMM, Âmin EF, El-Tahawy NF, Abdelrahman AM. Possible protective effect of diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol. 2016;9507563.
- Mattison PC, Soler-García AA, Das JR, Jerebtsova M, Perazzo S, Tang P et al. Role of circulating fibroblast growth factor-2 in lipopolysaccharide-induced acute kidney injury in mice. Pediatr Nephrol. 2012;27:469–83.
- Yücel E, Zengin MN, Özmen Ö, Çiftçi O. Doksorubusin kaynaklı kardiyotoksisite modelinde insülin benzeri büyüme faktörünün (igf-1) etkisinin araştırılması. Osmangazi Tıp Dergisi. 2024;46:945-54.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri (Diğer) |
| Bölüm | Araştırma |
| Yazarlar | |
| Proje Numarası | 2022SABE013. |
| Yayımlanma Tarihi | 30 Haziran 2025 |
| Gönderilme Tarihi | 24 Ocak 2025 |
| Kabul Tarihi | 23 Mayıs 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 50 Sayı: 2 |
