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Salt-Sensitive Hypertension COMMENTARIES See the related article beginning on page 1251. spread over 19 chromosomes had been found to contribute to hypertension in Salt-sensitive hypertension: if only rats (5), with at least 8 of these regions having effects on blood pressure in the it were as simple as rocket science Dahl salt-sensitive strain. It now seems clear that although this approach still Timothy L. Reudelhuber holds promise to uncover new targets in hypertension, it’s anything but sim- Clinical Research Institute of Montreal (IRCM), Montreal, Quebec, Canada ple. This is where the ability to knock- out genes in mice comes in handy. In J. Clin. Invest. 111:1115–1116 (2003). doi:10.1172/JCI200318397. the current issue, Ni et al. show that mice having an impaired ability to make γ-melanocyte–stimulating hor- What? Salt and hypertension? Again? If for several forms of hyper- and hypoten- mone (γ-MSH) exhibit salt-sensitive your attention drifted and you haven’t sion including Liddle, Bartter, and hypertension (2). been able to follow the debate for the Gitelman syndromes (reviewed in ref. 3). γ-MSH is a small peptide hormone last 30 years, I’d highly recommend Nevertheless, there’s no clear evidence to that is clipped out of the middle of the reading the 1998 Science article appro- date that the same genes that cause larger protein precursor proopiome- priately entitled “The (political) science these disorders play a significant role in lanocortin (POMC) by prohormone of salt” (1). Both the original article and essential hypertension. But wait, maybe convertase 2 (PC2) (Figure 1). Expres- the heated responses it generated are we just need to do a better job of sub- sion of POMC in the pituitary gland more entertaining than a ringside seat classifying patients and regulating their results in the release of several hor- at a Saturday night wrestling match. diets when we do genetic screens. As an mones, including the melanocortins, Why can’t we agree on whether dietary alternative and presumably simpler into the circulation while its expression salt is good or bad for people (or nei- approach, animal models have been in the hypothalamus and brainstem ther)? Some have suggested that the dif- used. In the early 1960s, Dahl and col- leads to production of melanocortiner- ficulty lies in the fact that the general leagues reported that they had bred rats gic neurotransmitters. In normal mice, population should be subclassified as characterized by a salt-sensitive form of γ-MSH increases in the circulation salt “responders” and “non-respon- hypertension (4). These rats have been when the animals are placed on a high- ders”. Another possibility, strengthened the subject of hundreds of research salt diet. In contrast, in PC2-knockout by the work of Ni et al. (2) in this issue studies aimed at defining the genes and mice γ-MSH does not increase and the of the JCI, is that additional hormonal proteins responsible for salt-sensitivity. mice develop hypertension. Of course factors modulate our salt sensitivity, In spite of the fact that genetic hetero- this alone would not constitute strong making it a moving target. geneity and diet can be taken out of the evidence for the role of γ-MSH since equation with this approach, as of 3 PC2 is involved in generating a lot of A tough nut to crack years ago 24 chromosomal regions other peptide and protein hormones Hormonal modulation of salt balance and blood volume is an indisputable truth in physiology. But does it play a critical role in hypertension? Genetic evidence certainly supports the possi- bility that it can. In humans, rare genet- ic disorders of salt transport in the kid- ney have been shown to be responsible Address correspondence to: Timothy L. Reudelhuber, Clinical Research Institute of Montreal (IRCM), 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada. Phone: (514) 987-5716; Fax: (514) 987-5717; E-mail: [email protected]. Conflict of interest: The author has declared Figure 1 that no conflict of interest exists. Schematic representation of the cleavage of pituitary proopiomelanocortin (POMC) by pro- Nonstandard abbreviations used: γ-melanocyte–stimulating hormone hormone convertase (PC) enzymes 1 and 2. Generated peptides include α-, β-, and γ-mela- (γ-MSH); proopiomelanocortin (POMC); nocyte–stimulating hormone (MSH), β- and γ- lipotropic hormone (LPH), adrenocorti- prohormone convertase (PC); melanocortin cotropic hormone (ACTH), β-endorphin (β-END), and the amino-terminal (NT), joining (JP), receptor (MC-R). and CLIP peptides. Note that the release of γ-MSH requires a cleavage by PC2 at both ends. The Journal of Clinical Investigation | April 2003 | Volume 111 | Number 8 1115 including insulin, glucagon, and so- (b) modulation of corticosterone levels tive hypothesis to test in a field where matostatin. However, the authors also (MC2-R); (c) appetite suppression and salient explanations are scarce. show that the hypertension seen in the metabolic activation (MC4-R); (d) ther- high-salt–fed PC2-knockout animals moregulation and water repulsion 1. Taubes, G. 1998. The (political) science of salt. Science. 281:898–901, 903–907. can be corrected by administration of a (MC5-R); and (e) inflammation (MC1-R 2. Ni, X.-P., Pearce, D., Butler, A.A., Cone, R.D., synthetic γ-MSH analogue and that the and MC3-R). It’s easy to imagine that and Humphreys, M.H. 2003. Genetic disrup- tion of γ-melanocyte–stimulating hormone sig- same results are seen in mice in which several of these responses might have naling leads to salt-sensitive hypertension in the γ-MSH receptor, melanocortin masked or complicated the analysis of the mouse. J. Clin. Invest. 111:1251–1258. receptor 3 (MC3-R), is knocked out. So blood pressure effects of γ-MSH. doi:10.1172/JCI200316993. 3. Lifton, R.P., Gharavi, A.G., and Geller, D.S. 1998. why hasn’t γ-MSH been implicated in Does this mean that γ-MSH is the Molecular mechanisms of human hypertension. salt-sensitive hypertension until now? cause of salt-induced hypertension in Cell. 281:545–556. 4. Dahl, L.K., Heine, M., and Tassinari, L. 1962. Role Part of the reason is certainly the multi- humans? Not by a long shot! The of genetic factors in susceptibility to experimen- tude of neuroendocrine signals mediat- knockout of other mouse genes, tal hypertension due to chronic excess salt inges- ed by the other peptides produced along including those for atrial natriuretic tion. Nature. 194:480–482. 5. Rapp, J.P. 2000. Genetic analysis of inherited with γ-MSH when POMC is processed peptide (6) and its receptor (7), the hypertension in the rat. Physiol. Rev. 80:135–172. (Figure 1), making it hard to isolate prostaglandin receptor EP2 (8), and 6. John, S.W., et al. 1995. Genetic decreases in atrial natriuretic peptide and salt-sensitive hyperten- γ-MSH–specific actions in a physiologi- the bradykinin receptor (9), also leads sion. Science. 267:679–681. cal setting. In fact, 5 receptors have been to salt-sensitive hypertension. Howev- 7. Oliver, P.M., et al. 1998. Natriuretic peptide recep- identified to date — MC1-R, MC2-R, er, none of these as yet has been linked tor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc. Natl. MC3-R, MC4-R, and MC5-R — for the to the condition in humans. Moreover, Acad. Sci. U. S. A. 95:2547–2551. melanocortin hormones alone, with the existence of γ-MSH in humans is 8. Kennedy, C.R., et al. 1999. Salt-sensitive hyper- more possibly to come. These receptors still a matter of some debate. Never- tension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat. Med. have a broad tissue distribution and they theless, the possibility that hormones 5:217–220. mediate a range of physiological respons- with both central and peripheral 9. Alfie, M.E., Yang, X.P., Hess, F., and Carretero, O.A. 1996. Salt-sensitive hypertension in es depending on their location. These actions like γ-MSH could cause our bradykinin B2 receptor knockout mice. Biochem. include: (a) pigmentation (MC1-R); salt-sensitivity to fluctuate is an attrac- Biophys. Res. Commun. 224:625–630. See the related article beginning on page 1161. efficiently reject tumor transplants from immunodeficient hosts, the exper- Coordinated tumor immunity iments support the idea that the immune system functions as an extrin- sic tumor suppressor. Consistent with Glenn Dranoff this concept, clinical-pathologic investi- gations established a strong association Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA between the presence of dense intratu- moral T cell infiltrates and favorable J. Clin. Invest. 111:1116–1118 (2003). doi:10.1172/JCI200318359. clinical outcomes in patients with malignant melanoma or carcinomas of the colon, kidney, and ovary (5, 6). The most important achievement of transformation-associated stress genes Other work indicates, though, that cancer immunology thus far may be commonly provokes innate immune tumors may subvert the immune sys- the development of robust techniques reactions (3). Together, these findings tem to facilitate disease progression for the identification of tumor anti- unveil a previously unsuspected breadth (7). Unresolved inflammation, whe- gens (1, 2). This work underlies our of immune recognition in tumor ther due to infection, autoimmunity, current understanding that cancer bearing hosts. or environmental agents, markedly patients frequently generate specific The characterization of cancer cell increases the risk of cancer. Dysregu- cellular and humoral antitumor antigenicity has fueled efforts to delin- lated cytokine production promotes responses. Moreover, the expression of eate protective immune-effector mech- cell proliferation and attenuates anisms. The task is complicated by the apoptosis.
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