RESUMO
Acute kidney injury (AKI) is a public health burden with increasing morbidity and mortality rates and health care costs. Acute tubular necrosis (ATN) is the most common cause of AKI. Cisplatin (CIS) is a platinum-based chemotherapeutic agent used in the treatment of a wide variety of malignancies such as lung, breast, ovary, testis, bladder, cervix, and head and neck cancers. Autophagy plays an important role in AKI. Galectin-3 (Gal-3) is significantly increased in renal tubules in AKI; however, its role in autophagy is not well understood. Male C57B6/J and B6.Cg-Lgals3
Assuntos
Injúria Renal Aguda , Necrose do Córtex Renal , Animais , Masculino , Camundongos , Autofagia , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Galectina 3/genética , Rim , NecroseRESUMO
BACKGROUND/AIMS: Acute kidney injury (AKI) is a public health burden with increasing morbidity, mortality and health care cost. It is associated with increased risk for the development of chronic kidney disease and death. Acute tubular necrosis (ATN) is the most common cause of AKI. Apoptosis and tissue necrosis play an important role in ATN. Galectin 3 (GAL-3), a beta galactoside binding lectin, is known to have a role in inflammation, apoptosis and oxidative stress but its role in cisplatin induced acute tubular necrosis is not clearly elucidated. METHODS: Male C57B6-J and C57BL-6 -GAL-3 knock-out mice were used to induce ATN using cisplatin mouse model of acute tubular necrosis. GAL-3 expression, apoptotic, necrotic and necroptotic proteins in kidneys were measured using standard histologic, immunohistochemical, and enzyme-linked immunosorbent assay techniques. Data were presented as mean ± S.E. Statistically significant differences (p<0.05) was calculated between experimental groups and corresponding control groups by one-way analysis of variance. RESULTS: There was a significant increase in GAL-3 in kidneys of cisplatin treated GAL-3 wild mice when compared with its control mice. In addition, there were significant higher percentage of ATN, higher levels of plasma urea and creatinine, and higher levels of cathepsin B and cathepsin D, in kidneys of cisplatin-treated GAL-3 KO mice than cisplatin-treated GAL-3 wild mice. Likewise, there were significant higher levels of necroptosis proteins RIPK1, RIPK3, and MLKL in kidneys of cisplatin-treated GAL-3 KO mice than cisplatin-treated GAL-3 wild mice. Moreover, there were significant higher levels of kidney pro-apoptotic proteins; cleaved caspase-3, cleaved PARP, TRAIL and FAS in cisplatin treated GAL-3 KO mice when compared with cisplatin treated GAL-3 wild mice. CONCLUSION: GAL-3 can affect cell survival and death through its interaction with necroptotic, apoptotic and pro-survival proteins in renal tubules during cisplatin-induced acute tubular necrosis.
Assuntos
Injúria Renal Aguda/metabolismo , Cisplatino/efeitos adversos , Galectina 3/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Túbulos Renais/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Animais , Cisplatino/farmacologia , Galectina 3/genética , Humanos , Proteínas Inibidoras de Apoptose/genética , Túbulos Renais/patologia , Camundongos , Camundongos Knockout , NecroseRESUMO
BACKGROUND/AIMS: Galectin 3 (GAL-3) is a beta galactoside binding lectin that has different roles in normal and pathophysiological conditions. GAL-3 has been associated with heart failure and was linked to increased risk of death in a number of studies. GAL-3 was found to be up regulated in animal models of heart failure as well as myocardial infarction (MI). The objective of his study is to test if high GAL-3 after myocardial infarction has a protective role on the heart through its anti-apoptotic and anti-necrotic functions. METHODS: Male C57B6/J mice and GAL-3 knockout (KO) mice were used for permanent ligation of the left anterior descending artery of the heart to create infarction in the anterior myocardium. Heart and plasma samples were collected 24 hours after the induction of MI and were used for immunohistochemistry, Tunnel procedure, electron microscopy and enzyme linked immunosorbent assay (ELISA). RESULTS: Our results show that the significant increase in GAL-3 levels in the left ventricle at 24-hour following MI is associated with significant lower levels of pro-apoptotic proteins; cytochrome c, Bax, annexin V, cleaved caspase-3 and a higher levels of anti-apoptotic protein Bcl2 in GAL-3 wild MI group than GAL-3 KO group. We also have identified the anti-apoptotic activity of GAL-3 is mediated through a significant increase in Akt-1, NF kappa-B and beta- catenin proteins. In addition, we have identified the antiapoptotic activity is mediated through a significant lower levels of cathepsin-D protein. CONCLUSION: We conclude that the increased levels of GAL-3 at 24-hour following MI regulate antiapoptotic mechanisms in the myocardium that will shape the future course of the disease. We also identified that the anti-apoptotic mechanisms are likely mediated through interaction of GAL-3 with Akt-1, NF kappa-B, beta- catenin and cathepsin D proteins.