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Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain.
Ferrandi, Mara; Molinari, Isabella; Rastaldi, Maria Pia; Ferrari, Patrizia; Bianchi, Giuseppe; Manunta, Paolo.
Afiliação
  • Ferrandi M; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy (M.F., I.M., P.F.); Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCC San Raffaele Scientific Institute, Milan, Italy (M.F., I.M., P.M.); Renal Research Laboratory, Fondazione IRCCS Ca' G
  • Molinari I; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy (M.F., I.M., P.F.); Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCC San Raffaele Scientific Institute, Milan, Italy (M.F., I.M., P.M.); Renal Research Laboratory, Fondazione IRCCS Ca' G
  • Rastaldi MP; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy (M.F., I.M., P.F.); Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCC San Raffaele Scientific Institute, Milan, Italy (M.F., I.M., P.M.); Renal Research Laboratory, Fondazione IRCCS Ca' G
  • Ferrari P; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy (M.F., I.M., P.F.); Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCC San Raffaele Scientific Institute, Milan, Italy (M.F., I.M., P.M.); Renal Research Laboratory, Fondazione IRCCS Ca' G
  • Bianchi G; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy (M.F., I.M., P.F.); Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCC San Raffaele Scientific Institute, Milan, Italy (M.F., I.M., P.M.); Renal Research Laboratory, Fondazione IRCCS Ca' G
  • Manunta P; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy (M.F., I.M., P.F.); Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCC San Raffaele Scientific Institute, Milan, Italy (M.F., I.M., P.M.); Renal Research Laboratory, Fondazione IRCCS Ca' G
J Pharmacol Exp Ther ; 351(2): 278-87, 2014 Nov.
Article em En | MEDLINE | ID: mdl-25187430
ABSTRACT
Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant ß-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducin- and ouabain-activated Na,K-ATPase, may protect podocytes from adducin- and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant ß-adducin and ouabain hypertensive rats were orally treated with 100 µg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant α-adducin or ß-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10(-9) M ouabain were cultured with 10(-9) M rostafuroxin. The results indicated that mutant ß-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant ß-adducin- and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant ß-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ouabaína / Proteinúria / Variação Genética / Proteínas de Ligação a Calmodulina / Podócitos / Androstanóis Limite: Animals Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ouabaína / Proteinúria / Variação Genética / Proteínas de Ligação a Calmodulina / Podócitos / Androstanóis Limite: Animals Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 2014 Tipo de documento: Article