Jean-Marc Lalouel
Professor of Human Genetics
D.Sc. University of Paris
M.D. University of Paris
Research
Essential hypertension (EH) is a very common condition likely to represent a heterogeneous set of disorders, each determined by several interacting factors, including genes, diet and lifestyle. We have suggested that molecular variants of the angiotensinogen gene (AGT) constitute inherited predisposition to the development of EH in humans. Our initial evidence rested on three observations in each of two independent samples of caucasian subjects: (1) hypertensive siblings inherited the same parental copy of the AGT gene more often than expected by chance; (2) a common variant of the gene, coding for threonine instead of methionine at position 235 of the mature protein (T235), occurred more often among hypertensive than among normotensive subjects; (3) plasma levels of AGT were significantly elevated among subjects carrying this molecular variant.
Of the many systems involved in blood pressure control, the renin-angiotensin system was selected for investigation because of its central role in salt and water homeostasis and in the maintenance of vascular tone. Our working hypothesis is that molecular variants of the AGT gene affecting expression or function of the protein may predispose carriers to a salt-sensitive form of EH through a mild over-reactivity of the renin-angiotensin system in response to sodium excess and environmental stressors. In collaboration with Japanese scientists, we have found a significant association between hypertension and the AGT variant T235 among Japanese subjects. The high prevalence of hypertension and cerebro-vascular disease, as well as the high salt intake which characterizes the population, lend further support to the hypothesis that the pathogenesis of an AGT-induced hypertension involves sodium homeostasis. We have also incriminated this genetic variant in preeclampsia, a common disorder of pregnancy.
The focus of our work now is to understand how a small but sustained increase in AGT expression can lead to EH. Specific issues that we are addressing are: what is the molecular variant involved? What is the physiological mechanism for AGT-dependent elevation of arterial pressure? Is global or tissue-specific overexpression relevant for development of the phenotype? To address the last question, we are developing transgenic mouse models of tissue-specific overexpression. These investigations have led us to concentrate on renal physiology, and this has led us to delineate a new model that emphasizes the role of a paracrine renin-angiotensin system in the regulation of sodium reabsorption along the entire nephron, including the novel finding that renin is expressed in a distal nephron segment. We are now probing the function of renin at this site by genetic manipulations. Because of the significance of genetic background in expression of cardiovascular phenotypes in the mouse, we have also initiated a study of the genetics of sodium sensitivity in this animal model. Indeed, when we overexpressed AGT in liver, we observed increased in plasma AGT and blood pressure in mouse of a sodium-sensitive background, but not in sodium-resistant strains.
In collaboration with Robert Weiss, we have identified another common variant in a gene that plays a critical role in the regulation of the epithelial sodium channel in the kidney. Surprisingly, the polymorphism controls the formation or a previously unidentified isoform that encodes a unique domain essential for the subcellular targeting of the protein. Clinical correlations are being unraveled, and all evidence suggests that together we have had the good fortune to identify another common genetic predisposition to essential hypertension. Work at the molecular cellular, and the entire organism is already under way.
References
1. Gociman B, Rohrwasser A, Lantelme P, Cheng T, Hunter G, Monson S, Hunter J, Hillas E, Lott P, Ishigami T, Lalouel J-M (2004) Expression of angiotensinogen in proximal tubule as a function of glomerular filtration rate. Kidney Int. June; 65:2153-2160
2. Rohrwasser A, Ishigami T, Gociman B, Lantelme P, Morgan T, Cheng T, Hillas E, Zhang S, Ward K, Bloch-Faure M, Meneton, P, Lalouel J-M (2003) Renin and kallikrein in connecting tubule of mouse. Kidney Int. Dec;64(6):2155-2162
3. Lalouel, J-M (2003) Large-scale search for genes predisposing to essential hypertension. Am J Hypertens Feb;16(2):163-6
4. Rohrwasser A, Zhang S, Dillon HF, Inoue I, Callaway CW, Hillas E, Lalouel JM (2002) Contribution of Sp1 to initiation of transcription of angiotensinogen. J Hum Genet May;47(5):249-56
5. Lantelme P, Rohrwasser A, Gociman B, Hillas E, Cheng T, Petty G, Thomas J, Xiao S, Ishigami T, Herrmann T, Terreros DA, Ward K, Lalouel JM (2002) Effects of dietary sodium and genetic background on angiotensinogen and Renin in mouse. Hypertension May;39(5):1007-14
6. Lalouel JM, Rohrwasser A (2002) Power and replication in case-control studies. Am J Hypertens Feb;15(2 Pt 1):201-5
7. Nakajima T, Inoue I, Cheng T, Lalouel JM (2002) Molecular cloning and functional analysis of a factor that binds to the proximal promoter of human angiotensinogen. J Hum Genet 47(1):7-13
8. Nakajima T, Jorde LB, Ishigami T, Umemura S, Emi M, Lalouel JM, Inoue I (2002) Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet Jan;70(1):108-23
9. Dunn D, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt S, Leppert M, Lalouel J-M, Weiss R (2002) Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. J of Human Genet. 47(12):665-76
10. Lalouel, J-M, Rohrwasser A (2001) Development of genetic hypotheses in essential hypertension. J of Human Genetics 46:299-306
11. Lalouel J-M (2001) From genetics to mechanism of disease liability. Advances in Genetics Vol. 42:517-533 Academic Press
12. Lalouel J-M, Rohrwasser A, Terreros D, Morgan T, Ward K (2001) Angiotensinogen in essential hypertension: from genetics to nephrology. J Am Soc Nephrol 12:606-615
13. Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M, Cheng T, Ludwig EH, Sharma AM, Hata A, Jeunemaitre X, Lalouel J-M (1997) A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affect basal transcription in vitro. J Clin Invest 99(7):1-12
14. Inoue I, Rohrwasser A, Helin C, Jeunemaitre X, Crain P, Bohlender J, Lifton RP, Corvol P, Ward K, Lalouel J-M (1995) A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system. J Biol Chem 270(19):11430-6
15. Ward K, Hata A, Jeunemaitre X, Helin C, Nelson L, Namikawa C, Farrington PE, Ogasawara M, Suzumori K, Tomoda S, Berrebi S, Sasaki M, Corvol P, Lifton RP, Lalouel J-M (1993) A molecular variant of angiotensinogen associated with preeclampsia. Nature Genetics 4:59-61
16. Jeunemaitre X, Lifton RP, Hunt SC, Williams RR, Lalouel J-M (1992) Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension. Nature Genetics 1:72-75
17. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel J-M (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell 71:169-80
18. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel J-M (1992) A chimaeric 11b-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262-65
