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

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

来源：Journal of Molecular Medicine-JMM, 2010, 88(2): 203-217.

DOI：10.1007/s00109-009-0549-x

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

Adducins are cytoskeletal actin-binding proteins (alpha, beta, gamma) that function as heterodimers and heterotetramers and are encoded by distinct genes. Experimental and clinical evidence implicates alpha- and beta-adducin variants in hypertension and renal dysfunction. Here, we have addressed the role of alpha- and beta-adducin on glomerular function and disease using beta-adducin null mice, congenic substrains for alpha- and beta-adducin from the Milan hypertensive (MHS) and Milan normotensive (MNS) rats and patients with IgA nephropathy. Targeted deletion of beta-adducin in mice reduced urinary protein excretion, preceded by an increase of podocyte protein expression (phospho-nephrin, synaptopodin, alpha-actinin, ZO-1, Fyn). The introgression of polymorphic MHS beta-adducin locus into MNS (Add2, 529R) rats was associated with an early reduction of podocyte protein expression (nephrin, synaptopodin, alpha-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 alpha-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 beta-adducin (ADD2, 1797T, rs4984) with a significant interaction with alpha-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.

• 出版日期2010-2