\u3b1- and \u3b2-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy

Adducins are cytoskeletal actin-binding proteins (\u3b1, \u3b2, \u3b3) that function as heterodimers and heterotetramers and are encoded by distinct genes. Experimental and clinical evidence implicates \u3b1- and \u3b2-adducin variants in hypertension and renal dysfunction. Here, we have addressed the role of \u3b1- and \u3b2-adducin on glomerular function and disease using \u3b2-adducin null mice, congenic substrains for \u3b1- and \u3b2-adducin from the Milan hypertensive (MHS) and Milan normotensive (MNS) rats and patients with IgA nephropathy. Targeted deletion of \u3b2-adducin in mice reduced urinary protein excretion, preceded by an increase of podocyte protein expression (phospho-nephrin, synaptopodin, \u3b1-actinin, ZO-1, Fyn). The introgression of polymorphic MHS \u3b2-adducin locus into MNS (Add2, 529R) rats was associated with an early reduction of podocyte protein expression (nephrin, synaptopodin, \u3b1-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 \u3b1-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 \u3b2-adducin (ADD2, 1797T, rs4984) with a significant interaction with \u3b1-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