Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport.

Abstract

The adducin heterodimer is a protein affecting the assembly of the actin-based cytoskeleton. Point mutations in rat adducin ␣ ( F316Y ) and ␤ ( Q529R ) subunits are involved in a form of rat primary hypertension (MHS) associated with faster kidney tubular ion transport. A role for adducin in human primary hypertension has also been suggested. By studying the interaction of actin with purified normal and mutated adducin in a cell-free system and the actin assembly in rat kidney epithelial cells (NRK-52E) transfected with mutated rat adducin cDNA, we show that the adducin isoforms differentially modulate: ( a ) actin assembly both in a cell-free system and within transfected cells; ( b ) topography of ␣ V integrin together with focal contact proteins; and ( c ) Na-K pump activity at V max (faster with the mutated isoforms, 1281 Ϯ 90 vs 841 Ϯ 30 nmol K/ h · mg pt., P Ͻ 0.0001). This co-modulation suggests a role for adducin in the constitutive capacity of the epithelia both to transport ions and to expose adhesion molecules. These findings may also lead to the understanding of the relation between adducin polymorphism and blood pressure and to the development of new approaches to the study of hypertension-associated organ damage. ( J. Clin. Invest. 1996. 97:2815-2822.)

Genetics of arterial hypertension and hypotension

“…Early transfection studies with the mutant rat α-adducin (316Y) into renal cells revealed a rearrangement of the cytoskeleton (potentially by an accelerated actin polymerization) associated with an increased Na + /K + ATPase activity (Tripodi et al 1996). More recently, expression of rat and human α-adducin variants has been implicated in a reduced endocytosis of Na + /K + ATPase molecules (Efendiev et al 2004).…”

Antihypertensive therapy, the α-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study

“…7,12,[26][27][28][29][30][31][32] The overall evidence from these experimental and clinical studies indicates that Trp allele carriers have an increased risk of hypertension attributable to an innate stimulation of the sodium pump and enhanced renal tubular sodium reabsorption. 7,[33][34][35][36][37] However, most studies in humans suggest that mutation of the a-adducin gene on its own is insufficient to cause hypertension. 12 Indeed, the pathogenesis of high BP is complex, involves multiple genes, and lifestyle and environmental factors.…”

Role of the Gly460Trp polymorphism of the α-adducin gene in primary hypertension in Scandinavians

“…9 Transfection studies with cDNA from the MHS showed altered ability of adducin to interact with actin and increased maximum velocity of the sodium-potassium pump. 18 In humans, polymorphic markers flanking the ␣-adducin gene have been shown to be associated with primary hypertension in Italians 19 and linkage has been demonstrated between the ␣-adducin locus and primary hypertension in French families. 20 The tryptophane variant of a polymorphism in the ␣-adducin gene which codes for either glycine or tryptophane at codon 460 (Gly460Trp) has been associated with hypertension in Italian, French and Japanese populations.…”