October 23, 1997

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The National Institute of Diab etes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has granted Kenneth Bernstein, MD, professor of Pathology and Laboratory Medicine, a MERIT award in recognition of his –consistent and excellent contributions to sci entific knowledge."

MERIT (Method to Extend Research in Time) awards extend the normal time period for a research grant, providing a few outstanding investigators with the opportunity for long-term stable support that will enhance their continue d scientific creativity and lessen the administrative burdens of preparing and submitting grant applications.

The $2-million MERIT award is an eight-year grant extending Dr. Bernstein's original NIH grant awarded in 1988 when he first joined the Emory faculty. He also is an investigator under Emory's O'Brien Kidney Center NIH grant and principal investigator for three other NIH R01 grants.

During the past 10 years Bernstein and his colleagues have been responsible for a number of key s cientific discoveries that have transformed the way in which scientists view the renin-angiotensin system and its effects on cardiovascular function. In 1989 they became one of the first laboratories in the world to isolate and clone the gene for the angi otensin converting enzyme (ACE), which controls the production of angiotensin II³the link between the kidneys and blood pressure control (Journal of Biological Chemistry, 1989).

When blood pressure drops, the kidney attempts to counterbalance the drop by releasing the enzyme, renin. Renin in turn catalyzes the production of angiotensin, a hormone circulating in the blood. The ACE enzyme converts the inactive form of angiotensin-†antiotensin I† to angiotensin II, which is a powerful vasopressor (co nstricter of blood vessels).

Through its vasopressor action, angiotensin II raises blood pressure and, through a variety of physiologic effects, decreases fluid loss by the kidney. For example, angiotensin II stimulates the adrenal cortex to sec ret aldosterone, which regulates the body's electrolyte and water balance by promoting the retention of sodium (and therefore of water) and the excretion of potassium. The retention of water induces an increase in plasma volume and thus an increase in blo od pressure.

To further elucidate the effects of angiotensin, Bernstein, using a rodent model, isolated and cloned the gene encoding the receptor for angiotensin II (Nature 1991), which has become known as the AT1 receptor. This receptor h as since been demonstrated to be responsible for virtually all of the physiologic and cardiovascular effects of angiotensin II. The importance of the AT1 receptor in basic science research is evident from the more than 1,000 scientific articles that have been published since 1993 detailing its biology.

"Everybody would accept the fact that while blood pressure is very complex and multifactorial," says Bernstein, "in the middle is angiotensin II with its many effects on smooth muscle, th e heart, the kidney, the adrenal, the brain and the gut, all of which act coordinately to maintain blood pressure. By understanding and cloning this receptor, we have given people an immense, powerful tool to study the regulation of blood pressure and to understand this multisystem process that maintains our blood."

In a 1994 article in Nature, Bernstein described the unique messaging pathway used by the AT1 receptor to send messages from the cell surface to the cell nucleus. In respon se to angiotensin II, the AT1 receptor activates an intracellular messenger called the Jak2 kinase, which in turn initiates a cascade of signals often referred to as the Jak-STAT pathway. Through this cascading pathway, messages are sent from the cell sur face to the cell nucleus. Although receptors for several other kinds of cell mediators are known to use this pathway, the AT1 receptor is a member of the class of receptors called "seven transmembrane receptors," or "G-protein associated receptors."

Whereas scientists previously believed these receptors used a different type of signaling, Bernstein's work was the first observation that any of the seven transmembrane receptors was capable of activating the Jak-STAT pathway. Because the seven transmembrane receptors are a superfamily of hundreds of receptors, discovery of this unique messaging system has given researchers insight into previously unknown signaling pathways for the entire class of receptors, which include those for a variety of critical bodily functions.

ACE in Reproductive Biology

One of the most interesting aspects of ACE biology is the two different manifestations, or isozymes, of the enzyme. The terms for these two different isozymes-somatic ACE an d testis ACE-were first coined by Bernstein's group. Somatic ACE , found in the lungs, the kidneys, and in blood vessels throughout the body, is the form commonly associated with control of blood pressure, but the other form-testis ACE-is made exclusively by developing male sperm cells.

Bernstein's study of testis ACE has focused on two critical dilemmas: (1) How is this unique form of ACE made in such a restricted, tissue-specific fashion? and (2) Is there any real physiological role of testis A CE in male reproductive biology? He answered the first question through his discovery that the transcription of testis ACE in the mouse is initiated by a testis-specific promoter located within a certain portion of the somatic ACE gene-a finding later con firmed in the human gene.

To determine whether testis ACE has any real importance in male reproduction, Bernstein created recombinant knockout mice containing no somatic or testis ACE gene. He found that the male knockout mice fathered litters w ith much smaller numbers of offspring than those of typical wild mice, suggesting that testis ACE is necessary for full male fertility (Laboratory Investigation, 1994). In addition, mice lacking somatic ACE have an unusual renal phenotype characterized by the inability to effectively concentrate urine.

"These are very fundamental questions that go to the very basis of what makes one cell different from another cell," says Bernstein. "By understanding the function of testis ACE, we get a real ins ight into the basic makeup of what we are, which is a creature of many different tissues, each of which is responsible for a functionality." Bernstein's current research focuses on three areas: the intracellular signals initiated when angiotensin II bind s to the AT1 receptor; creating new knockout mice to understand more about the physiologic role of ACE in reproduction and blood pressure; and the biochemistry of testis ACE expression as a model of tissue-specific gene expression.

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Last Updated: October 19, 1997