Jean-Marc Lalouel, M.D., D.Sc.
Professor

Contribution to Society

Final elucidation of the process by which molecular variants of angiotensinogen predispose to hypertension should contribute to better diagnosis, treatment, and prevention of some forms of essential hypertension as well as certain complications of pregnancy.

Research Summary

Essential hypertension is a very common condition likely to represent a heterogenous set of disorders, each determined by several interacting factors, including genes, diet and lifestyle. We have suggested that molecular variants of the angiotensinogen gene constitute inherited predisposition to the development of essential hypertension 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 angiotensinogen 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 angiotensinogen 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 angiotensinogen gene affecting expression or function of the protein may predispose carriers to a salt-sensitive form of essential hypertension 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 angiotensinogen variant T235 among Japanese subjects. The high prevalence of hypertension and cerebrovascular disease, as well as the high salt intake which characterizes the population, lend further support to the hypothesis that the pathogenesis of an angiotensinogen-induced hypertension involves sodium homeostasis.

Angiotensinogen expression is stimulated by estrogen, and pregnancy or oral contraceptives induce hypertension in some women. In collaboration with Kenneth Ward, we showed that the T235 variant of angiotensinogen occurred at higher frequency in women with preeclampsia than in women with normal pregnancy outcome.

Together, these observations strongly support the hypothesis that variants of the angiotensinogen gene predispose individuals to a form of hypertension which can become manifest early in life under the exceptional physiological stress of pregnancy or at a mature age as a consequence of moderate but chronic stimulation of the renin-angiotensin system.

The focus of our work now is to understand how a small but sustained increase in angiotensinogen expression can lead to essential hypertension. Specific issues that we are addressing are: what is the molecular variant involved? What is the physiological mechanism for angiotensinogen-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. The function of renin at this site will now be probed 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.

Recent Publications

Rohrwasser A, Ishigami T, Gociman B, Lantelme P, Morgan T, Cheng T, Hillas E, Zhang S, Ward K, Bloch-Faure M, Meneton P, Lalouel JM (2003) Renin and kallikrein in connecting tubule of mouse. Kidney Int. 64(6):2155-62.

Lalouel JM (2003) Large-scale search for genes predisposing to essential hypertension. Am J Hypertens 16(2):163-6.

Dunn DM, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt SC, Leppert MF, Lalouel JM, Weiss RB (2002) Common variant of human NEDD4L activates a cryptic splice to form a frameshifted transcript. J Hum Genet 47(12):665-76.

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. 47(5):249-56.

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 39(5):1007-14.

Lalouel JM, Rohrwasser A (2002) Power and replication in case-control studies. Am J Hypertens 15(2 Pt 1):201-5.

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.
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. 70(1):108-23.

Lalouel JM, Rohrwasser A (2001) Development of genetic hypotheses in essential hypertension. J Hum Genet. 46(6):299-306. Review.

Lalouel JM, Rohrwasser A, Terreros D, Morgan T, Ward K (2001) Angiotensinogen in essential hypertension: from genetics to nephrology. J Am Soc Nephrol 12(3):606-15. Review.

Lalouel JM (2001) From genetics to mechanism of disease liability. Adv Genet. 42:517-33. Review.

Rohrwasser A, Morgan T, Dillon HF, Zhao L, Callaway CW, Hillas E, Zhang S, Cheng T, Inagami T, Ward K, Terreros DA, Lalouel JM (1999) Elements of a paracrine tubular renin-angiotensin system along the entire nephron. Hypertension. 34(6):1265-74.

Nakajima T, Cheng T, Rohrwasser A, Bloem LJ, Pratt JH, Inoue I, Lalouel JM (1999) Functional analysis of a mutation occurring between the two in-frame AUG codons of human angiotensinogen. J Biol Chem. 274(50):35749-55.

Hunt SC, Province MA, Atwood LD, Sholinsky P, Lalouel JM, Rao DC, Williams RR, Leppert MF (1999) No linkage of the lipoprotein lipase locus to hypertension in Caucasians. J Hypertens.17(1):39-43.

Morgan T, Craven C, Lalouel JM, Ward K (1999) Angio-tensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spiral arteries in first-trimester decidua. Am J Obstet Gynecol. 180(1 Pt 1):95-102.