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
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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.
    Frontiers in Physiology 09/2015; 6:233. DOI:10.3389/fphys.2015.00233 · 3.53 Impact Factor
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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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    Frontiers in Physiology 08/2015; 6:227. DOI:10.3389/fphys.2015.00227 · 3.53 Impact Factor
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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. "
    Lei Mao ·
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    ABSTRACT: Genetic background of an individual can drastically influence an organism's response upon environmental stress and pathological stimulus. Previous studies in inbred rats showed that compared to Brown Norway (BN), Dahl salt-sensitive (SS) rat exerts strong hypoxia susceptibility. However, despite extensive narrow-down approaches via the chromosome substitution methodology, this genome-based physiological predisposition could not be traced back to distinct quantitative trait loci. Upon the completion and public data availabil-ity of PhysGen SS-BN consomic (CS) rat platform, I employed systems biology approach attempting to further our understanding of the molecular basis of genetic background effect in light of hypoxia response. I analyzed the physiological screening data of 22 CS rat strains under normoxia and 2-weeks of hypoxia, and cross-compared them to the parental strains. The analyses showed that SS-9 BN and SS-18 BN represent the most hypoxia-resistant CS strains with phenotype similar to BN, whereas SS-6 BN and SS-Y BN segregated to the direc-tion of SS. A meta-analysis on the transcriptomic profiles of these CS rat strains under hypoxia treatment showed that although polymorphisms on the substituted BN chromo-somes could be directly involved in hypoxia resistance, this seems to be embedded in a more complex trans-chromosomal genetic regulatory network. Via information theory based modeling approach, this hypoxia relevant core genetic network was reverse engi-neered. Network analyses showed that the protective effects of BN chromosome 9 and 18 were reflected by a balanced activation of this core network centering on physiological homeostasis. Presumably, it is the system robustness constituted on such differential net-work activation that acts as hypoxia response modifier. Understanding of the intrinsic link between the individual genetic background and the network robustness will set a basis in the current scientific efforts toward personalized medicine.
    Frontiers in Genetics 10/2012; 3. DOI:10.3389/fgene.2012.00208
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