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

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 hyperten-
sive (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 (phosphonephrin,
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.