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 (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.
Ferrandi
Mara
M
Prassis sigma-tau Research Institute, Settimo Milanese, Milan, Italy.
Cusi
Daniele
D
Molinari
Isabella
I
Del Vecchio
Lucia
L
Barlassina
Cristina
C
Rastaldi
Maria Pia
MP
Schena
Francesco Paolo
FP
Macciardi
Fabio
F
Marcantoni
Carmelita
C
Roccatello
Dario
D
Peters
Luanne L
LL
Armelloni
Silvia
S
Min
Li
L
Giardino
Laura
L
Mattinzoli
Deborah
D
Camisasca
Claudio
C
Palazzo
Fiorentina
F
Manunta
Paolo
P
Ferrari
Patrizia
P
Bianchi
Giuseppe
G
D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D051379:Mice; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D011507:Proteinuria / Q000235:genetics*; D051381:Rats; D012377:Rodentia; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D000099291:Adducins