α- and β-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy

Mara Ferrandi, Daniele Cusi, Isabella Molinari, Lucia Del Vecchio, Cristina Barlassina, Maria Pia Rastaldi, Francesco Paolo Schena, Fabio MacCiardi, Carmelita Marcantoni, Dario Roccatello, Luanne L. Peters, Silvia Armelloni, Li Min, Laura Giardino, Deborah Mattinzoli, Claudio Camisasca, Fiorentina Palazzo, Paolo Manunta, Patrizia Ferrari, Giuseppe Bianchi

Research output: Contribution to journalArticle

Abstract

Adducins are cytoskeletal actin-binding proteins (α, β, γ) that function as heterodimers and heterotetramers and are encoded by distinct genes. Experimental and clinical evidence implicates α- and β-adducin variants in hypertension and renal dysfunction. Here, we have addressed the role of α- and β-adducin on glomerular function and disease using β-adducin null mice, congenic substrains for α- and β-adducin from the Milan hypertensive (MHS) and Milan normotensive (MNS) rats and patients with IgA nephropathy. Targeted deletion of β-adducin in mice reduced urinary protein excretion, preceded by an increase of podocyte protein expression (phospho-nephrin, synaptopodin, α-actinin, ZO-1, Fyn). The introgression of polymorphic MHS β-adducin locus into MNS (Add2, 529R) rats was associated with an early reduction of podocyte protein expression (nephrin, synaptopodin, α-actinin, ZO-1, podocin, Fyn), followed by severe glomerular and interstitial lesions and increased urinary protein excretion. These alterations were markedly attenuated when the polymorphic MHS α-adducin locus was also present (Add1, 316Y). In patients with IgA nephropathy, the rate of decline of renal function over time was associated to polymorphic β-adducin (ADD2, 1797T, rs4984) with a significant interaction with α-adducin (ADD1, 460W, rs4961). These findings suggest that adducin genetic variants participate in the development of glomerular lesions by modulating the expression of specific podocyte proteins.

Original languageEnglish
Pages (from-to)203-217
Number of pages15
JournalJournal of Molecular Medicine
Volume88
Issue number2
DOIs
Publication statusPublished - Feb 2010

Keywords

  • Adducin
  • Genetic renal disease
  • Glomerular disease
  • IgA nephropathy
  • Podocytes
  • Proteinuria

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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    Ferrandi, M., Cusi, D., Molinari, I., Del Vecchio, L., Barlassina, C., Rastaldi, M. P., Schena, F. P., MacCiardi, F., Marcantoni, C., Roccatello, D., Peters, L. L., Armelloni, S., Min, L., Giardino, L., Mattinzoli, D., Camisasca, C., Palazzo, F., Manunta, P., Ferrari, P., & Bianchi, G. (2010). α- and β-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy. Journal of Molecular Medicine, 88(2), 203-217. https://doi.org/10.1007/s00109-009-0549-x