Chromosome substitution revels the genetic basis of Dahl salt-sensitive hypertension and renal disease. Am. J. Physiol

Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
American journal of physiology. Renal physiology (Impact Factor: 3.25). 09/2008; 295(3):F837-42. DOI: 10.1152/ajprenal.90341.2008
Source: PubMed


This study examined the genetic basis of hypertension and renal disease in Dahl SS/Mcwi (Dahl Salt-Sensitive) rats using a complete chromosome substitution panel of consomic rats in which each of the 20 autosomes and the X and Y chromosomes were individually transferred from the Brown Norway (BN) rat onto the Dahl SS/Mcwi genetic background. Male and female rats of each of the two parental and 22 consomic strains (10-12 rats/group) were fed a high-salt (8.0% NaCl) diet for 3 wk. Mean arterial blood pressure rose by 60 mmHg and urinary protein and albumin excretion increased 3- and 20-fold, respectively, in male SS/Mcwi rats compared with BN controls. Substitution of chromosomes 1, 5, 7, 8, 13, or 18 from the BN onto the SS/Mcwi background attenuated the development of hypertension, proteinuria, and albuminuria in male rats. In female rats, substitution of chromosomes 1 and 5 also decreased blood pressure, protein excretion, and albumin excretion. These studies also identified several chromosomes in male (6, 11, Y) and female (4, 6, 11, 19, 20) rats that reduced albuminuria without altering blood pressure. These data indicate that genes contributing to salt-sensitive hypertension are found on multiple chromosomes of the Dahl SS/Mcwi rat. Furthermore, this consomic rat panel provides a stable genetic platform that can facilitate further gene mapping by either linkage studies or the breeding of congenic and subcongenic rats.

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    • "This would have the consequence of increasing both renal NE release and NE-mediated sodium reabsorption leading to the observed sodium retention to drive the pathophysiology of salt-sensitivity. To confirm that impaired up-regulation of central Gαi 2 proteins impacts saltsensitivity in the DSS rat, we conducted studies using an 8- congenic DSS rat, which has chromosome 8 encoding the GNAI2 gene from the Brown Norway rat (Mattson et al., 2008). "
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    ABSTRACT: To counter the development of salt-sensitive hypertension, multiple brain G-protein-coupled receptor (GPCR) systems are activated to facilitate sympathoinhibition, sodium homeostasis, and normotension. Currently there is a paucity of knowledge regarding the role of down-stream GPCR-activated Gα-subunit proteins in these critically important physiological regulatory responses required for long-term blood pressure regulation. We have determined that brain Gαi2-proteins mediate natriuretic and sympathoinhibitory responses produced by acute pharmacological (exogenous central nociceptin/orphanin FQ receptor (NOP) and α2-adrenoceptor activation) and physiological challenges to sodium homeostasis (intravenous volume expansion and 1 M sodium load) in conscious Sprague-Dawley rats. We have demonstrated that in salt-resistant rat phenotypes, high dietary salt intake evokes site-specific up-regulation of hypothalamic paraventricular nucleus (PVN) Gαi2-proteins. Further, we established that PVN Gαi2 protein up-regulation prevents the development of renal nerve-dependent sympathetically mediated salt-sensitive hypertension in Sprague-Dawley and Dahl salt-resistant rats. Additionally, failure to up-regulate PVN Gαi2 proteins during high salt-intake contributes to the pathophysiology of Dahl salt-sensitive (DSS) hypertension. Collectively, our data demonstrate that brain, and likely PVN specific, Gαi2 protein pathways represent a central molecular pathway mediating sympathoinhibitory renal-nerve dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Further, impairment of this endogenous "anti-hypertensive" mechanism contributes to the pathophysiology of salt-sensitive hypertension.
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    • "The salt sensitivity of BP is mediated by several mechanisms involving the vessels , the brain , the kidneys and of course genetics factors ( Cowley , 1997 ; Weinberger , 2006a ; Sanada et al . , 2011 ) . Seminal experimental models such as those developed in the rat by Dahl and collaborators ( Dahl et al . , 1962 ; Mattson et al . , 2008 ) and the recent description of several monogenic forms of essential hypertension linking the development of hypertension to a renal tubular defect limiting the excretion of sodium have clearly demonstrated the crucial roles of genetic factors and renal sodium handling in the salt - sensitive phenotype ( Lifton , 1996 ; Ji et al . , 200"
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    ABSTRACT: Among the various strategies to reduce the incidence of non-communicable diseases reduction of sodium intake in the general population has been recognized as one of the most cost-effective means because of its potential impact on the development of hypertension and cardiovascular diseases. Yet, this strategic health recommendation of the WHO and many other international organizations is far from being universally accepted. Indeed, there are still several unresolved scientific and epidemiological questions that maintain an ongoing debate. Thus what is the adequate low level of sodium intake to recommend to the general population and whether national strategies should be oriented to the overall population or only to higher risk fractions of the population such as salt-sensitive patients are still discussed. In this paper, we shall review the recent results of the literature regarding salt, blood pressure and cardiovascular risk and we present the recommendations recently proposed by a group of experts of Switzerland. The propositions of the participating medical societies are to encourage national health authorities to continue their discussion with the food industry in order to reduce the sodium intake of food products with a target of mean salt intake of 5-6 grams per day in the population. Moreover, all initiatives to increase the information on the effect of salt on health and on the salt content of food are supported.
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    • "By this means, two hypoxia-resistant (SS-9BN and SS-18BN) and two hypoxia-susceptible CS strains (SS-6BN and SS-YBN) were confidently identified as those whose phenotype measurements segregate to either of the parental strains. This result is partially coherent to previous findings (Forster et al., 2003; Dwinell et al., 2005; Mattson et al., 2008). Contrary to my expectation, there was no biochemical alteration regarding either “plasma mean corpuscular hemoglobin content” or “plasma red blood cell” among parental strains or CS strains comparing hypoxia to normoxia condition. "
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