Pedro H F Gois1, Daniele Canale2, Rildo A Volpini2, Daniela Ferreira2, Mariana M Veras3, Vinicius Andrade-Oliveira4, Niels O S Câmara4, Maria H M Shimizu2, Antonio C Seguro2. 1. Laboratory of Medical Research - LIM12, Nephrology Department, University of São Paulo School of Medicine, São Paulo, Brazil. Electronic address: pedrogoismd@usp.br. 2. Laboratory of Medical Research - LIM12, Nephrology Department, University of São Paulo School of Medicine, São Paulo, Brazil. 3. Laboratory of Medical Research - LIM05, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil. 4. Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Abstract
BACKGROUND: Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI. METHODS: Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol. RESULTS: Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF2a (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis-associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade. CONCLUSIONS: Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication.
BACKGROUND:Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI. METHODS: Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol. RESULTS:Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF2a (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis-associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade. CONCLUSIONS:Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication.
Authors: Richard J Johnson; George L Bakris; Claudio Borghi; Michel B Chonchol; David Feldman; Miguel A Lanaspa; Tony R Merriman; Orson W Moe; David B Mount; Laura Gabriella Sanchez Lozada; Eli Stahl; Daniel E Weiner; Glenn M Chertow Journal: Am J Kidney Dis Date: 2018-02-27 Impact factor: 8.860
Authors: Monique Marques da Silva; Moisés Felipe Pereira Gomes; Elizabeth de Orleans Carvalho de Moura; Mariana Matera Veras; Melina Chiemi Kubota; Ana Paula Takano; Ana Carolina Cardoso Dos Santos; Carolina Gonçalves Dos Reis José; Graziele Aparecida da Silva Souza; Naiara Magalhães Cardoso; Debora Estadella; Rafael Herling Lambertucci; Alessandra Medeiros Journal: PLoS One Date: 2022-06-03 Impact factor: 3.752
Authors: Mariana Moura Nascimento; Desiree Rita Denelle Bernardo; Ana Carolina de Bragança; Maria Heloisa Massola Shimizu; Antonio Carlos Seguro; Rildo Aparecido Volpini; Daniele Canale Journal: Front Med (Lausanne) Date: 2022-08-04
Authors: Ana C de Bragança; Regina L M Moreau; Thales de Brito; Maria H M Shimizu; Daniele Canale; Denise A de Jesus; Ana M G Silva; Pedro H Gois; Antonio C Seguro; Antonio J Magaldi Journal: PLoS One Date: 2017-07-05 Impact factor: 3.240