Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Abstract

Bianchi, Giuseppe. Genetic variations of tubular sodium reabsorption leading to "primary" hypertension: from gene polymorphism to clinical symptoms. Am J Physiol Regul Integr Comp Physiol 289: R1536-R1549, 2005. doi:10.1152/ajpregu.00441.2005.-The definition of the most appropriate strategy to demonstrate causation of a given geneticmolecular mechanism in a complex multifactorial polygenic disease like hypertension is hampered by the underestimation of the complexity arising from the genetic and environmental interactions. To disentangle this complexity, we developed a strategy based on six steps: 1) isolation of a rodent model of hypertension (Milan hypertensive strain and Milan normotensive strain) that shares some pathophysiological abnormalities with human primary hypertension; 2) definition in the model of the sequence of events linking these abnormalities to a genetic molecular mechanism; 3) determination of the polymorphism of the three adducin genes discovered in the model both in rats and in humans; 4) comparison at biochemical and physiological levels between the rodent models and the hypertensive carriers of the "mutated" gene variants; 5) evaluation of the impact of the adducin genes in hypertension and its organ complications with association and linkage studies in humans, also considering the genetic and environmental interactions; and 6) development of a pharmacogenomic approach aimed at establishing the therapeutic benefit of a drug interfering with the sequence of events triggered by adducin and their effect's size. The bulk of data obtained demonstrates the importance of a multidisciplinary approach considering a variety of genetic and environmental interactions. Adducin functions within the cells as a heterodimer composed of a combination of three subunits. Each of these subunits is coded by genes mapping to different chromosomes. Therefore, the interaction among these genes, taken together with the interactions with other modulatory genes or with the environment, is indispensable to establish the adducin clinical impact. The hypothesis that adducin polymorphism favors the development of hypertension via an increased tubular sodium reabsorption is well supported by a series of consistent experimental and clinical data. Many mechanistic aspects, underlying the link between these genes and clinical symptoms, need to be clarified. The clinical effect size of adducin must be established also with the contribution of pharmacogenomics with a drug that selectively interferes with the sequence of events triggered by the mutated adducin.genes; blood pressure; Na-K pump; Na channel; adducin The difficulty lies, not only in the new ideas, but in escaping the old ones. J. M. Keynes STARLING'S LONG-LASTING concern was to use physiology as a means to bring basic science to the bedside. Indeed, by integrating the capillary fluid exchange with the cardiac pump function, Starling provided a substantial contribution to bridge the gap between the contemporary basic science of circulation and the clinical sympto...

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

“…In this context, we have contributed to unraveling the role of a polymorphism of the cytoskeletal protein adducin and high levels of endogenous ouabain (EO) in hypertension and glomerular podocyte damage, both in animal models and in patients (Bianchi et al, 1994;Bianchi, 2005;Manunta et al, 2009;Ferrandi et al, 2010a,b). These studies have shown that mutant a-adducin and ouabain activate Src tyrosine kinase and the Src-dependent Na,K-ATPase phosphorylation and its signaling network, associated with an overall increase of renal tubular sodium reabsorption and blood pressure (BP) (Ferrandi et al, 2010a).…”

Pharmacogenomics and Pharmacogenetics of Hypertension

“…Within this large distance, many haplotype blocks were included (39). Positive results were also obtained in 18 of 20 association studies that, in addition to BP, investigated variables that reflect body sodium or the renin-angiotensin system (16,26). Four of five studies (40 -44) showed an association between ␣-adducin polymorphism and organ damage in hypertensive individuals.…”

“…According to a PubMed literature search, after our initial report (16,26), at least 67 articles addressed the association between human hypertension and the ADD1 Trp allele. Six human (20,30 -34) linkage studies showed positive results when a DNA marker that mapped to 30 kb from the ADD1 locus or SNP of one of the three adducin genes was considered either alone or in combination with each other or angiotensinconverting enzyme D allele or salt intake.…”

“…Four of five studies (40 -44) showed an association between ␣-adducin polymorphism and organ damage in hypertensive individuals. There were mixed results from casecontrol studies or studies in predominantly normotensive populations that did not consider the above-mentioned variables (see [16,26] for a detailed discussion of this issue).…”

“…Our research group approached the dissection of this complexity throughout a series of studies on animal models and patients at different levels of biologic organization: Whole body, organ, cell, subcellular structures, protein, and genes (16). These studies led to the identification of adducin polymorphism as one of the genetic mechanism that, by modulating the constitutive capacity of tubular cell to reabsorb sodium, may favor the development of hypertension with its organ complications.…”