Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain

Mara Ferrandi, Isabella Molinari, Maria Pia Rastaldi, Patrizia Ferrari, Giuseppe Bianchi, Paolo Manunta

Research output: Contribution to journalArticle

Abstract

Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant β-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 adducinand ouabain-activated Na,K-ATPase, may protect podocytes from adducin-and ouabain-nduced 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 β-adducin and ouabain hypertensive rats were orally treated with 100 μg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant a-adducin or β-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10-9M ouabain were cultured with 10-9M rostafuroxin. The results indicated that mutant β-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 culturedpodocytes with rostafuroxin, reverted mutant β-adducin-and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant β-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. Copyright

Original languageEnglish
Pages (from-to)278-287
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume351
Issue number2
DOIs
Publication statusPublished - Nov 1 2014

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

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