Stephen A. Katz, Ph.D. Associate Professor of Physiology

Research Overview

Work in my lab centers around the Renin-Angiotensin System (RAS). Renin is both a hormone and an enzyme. In the “Classical RAS”, the kidney secretes renin into the bloodstream. Renin then catalyzes the formation of angiotensin I from hepatically produced angiotensinogen, and angiotensin I is immediately converted to angiotensin II, the effector molecule of the RAS. Renin is the primary controlled variable of the RAS- the higher the plasma renin level, the greater the circulating level of Angiotensin II. Angiotensin II is a major regulator of blood pressure and many salt and water balance systems such as the aldosterone hormone system. Interestingly, angiotensin II is also a very important cardiac growth factor, and is involved in the growth and differentiation of adipose tissue.

Previous hypotheses in my lab were concerned with the biosynthesis, storage, secretion, site of action, and degradation of renin. A past major interest in my lab was examining variable post-translational glycosylation of renin. Different oligosaccharide attachments (N-linked glycosylation) to the polypeptide chain of renin help determine renal renin storage, the secretion and degradation rates of renin, as well as renin distribution in the blood vessel wall, myocardium, and presumably adipose tissue.

This is diagramed below.

Over the past 10 years, my research has focused on the cardiac renin- angiotensin system (Cardiac RAS). In this system, circulating renin from the kidney (Classical RAS) diffuses into the cardiac wall and catalyzes the formation of angiotensin I within the myocardial interstitium. Angiotensin II, formed from angiotensin I, is a major stimulus for cardiac growth, and causes ventricular hypertrophy and remodeling of the cardiac wall. Although some cardiac hypertrophy can be adaptive, too much hypertrophy is maladaptive. In essence, in the presence of high levels of Angiotensin II, the heart can grow too much and become an inefficient pump. This is known as heart failure. My lab is has an interest in trying to measure the contribution of the Cardiac RAS to left ventricular hypertrophy for a wide range of cardiac diseases. We are also very interested in a "renin-look-a-like" enzyme called cathepsin D. Cathepsin D is a lysosomal enzyme with a high sequence homology to renin, and can display renin-like enzymatic activity (angiotensin I generation). Since cathepsin D is present in cardiac and adipose tissue, the contribution of cathepsin D to the cardiac or adipose RAS is a focus point of the lab. The figure below shows the renin and cathepsin D isoelectric focusing fingerprints for normal (control) rat myocardium, and myocardium taken from an animal with no kidneys (bilateral nephrectomy, or BNX).

Experiments are accomplished at the molecular, cellular, and whole animal level. Experiments with human volunteers in a clinical research laboratory setting are also performed.

Most recent research experience:

Although the cardiac RAS remains as a research area in my lab, the major thrust of our current work is now addressing the adipose RAS. In the adipose RAS, angiotensin II is responsible in part for adipocyte differentiation and insulin sensitivity. My lab is currently trying to understand the interaction between the circulating “Classical RAS” and the “local adipose RAS” and how the adipose RAS is involved in adipose biology. More specifically, we are examining the possible discordance between mRNA and protein expression for the adipose RAS and the true site of synthesis for adipose RAS components. Adipose tissue may contribute RAS components to the classical circulating RAS system, and adipose tissue may also sequester circulating RAS components.

Some Relevant Publications

Katz SA, Opsahl JA, Lunzer ML, Forbis L, Hirsch AT. Effect of Bilateral nephrectomy on active renin, angiotensinogen, and renin glycoforms in plasma and myocardium. Hypertension. 1997; 30(1):259-266.

Heller LJ, Opsahl JA, Wernsing SE, Saxena R, Katz SA. Myocardial and plasma renin-angiotensinogen dynamics during pressure-induced cardiac hypertrophy. Am J of Physiol (Reg. Integ. Comp. Physiol.) 1998; 274:R849-R856.

Katz SA. Some teaching tips on the mechanisms of urinary concentration and dilution: countercurrent multiplication be damned. American Journal of Physiology (Advances in Physiology Education 20). 1998; 275:S195-S205.

Hirsch AT, Opsahl JA, Lunzer MM, Katz SA. Active Renin and Angiotensinogen in the Cardiac Interstitial Fluid Following Myocardial Infarction. American Journal of Physiology (Heart & Circulatory Physiol. 45). 1999; 276:H1818-H1826.

Katz, SA, Opsahl JA, Wernsing SE, Forbis LM, Smith J, Heller LJ. Myocardial renin is neither necessary nor sufficient to initiate or maintain ventricular hypertrophy. American Journal of Physiology (Regulatory Integrative Comp. Physiol.). 2000; 278:R578-R586.

Heller L.J., Katz SA. Influence of enalapril on pressure-overload cardiac hypertrophy in low and normal renin states in female rats. Life Sciences. 2000; 66:1423-1433.

Katz SA, Opsahl JA, and Forbis, L.M. Myocardial enzymatic activity of renin and cathepsin D before and after bilateral nephrectomy. Basic Research in Cardiology. 2001; 96:659-668.

Osborn JW, Ariza-Nieto P, Collister JP, Soucheray S, Zimmerman B, and Katz SA. Responsiveness versus Basal Activity of Plasma Angiotensin II as a Determinant of Arterial Pressure Salt-Sensitivity. Am J Physiol (Heart Circ Physiol). 2003: 285:H2142-H2149.

Naseem HR, Hedegard W, Henry TD, Lessard J, Sutter K, and Katz SA. Plasma Cathepsin D Isoforms and Their Active Metabolites Increase after Myocardial Infarction and Contribute to Plasma Renin Activity. Basic Research in Cardiology. 2005; 100:139-146.

Jacob F, LaBine BG, Ariza P, Katz SA, and Osborn JW. Renal denervation causes chronic hypotension in rats: Role of ß1 adrenoceptor activity. Clinical & Experimental Pharmacology & Physiology. 2005; 32:255-262.

Teaching

I like to teach and I teach at least 50% of my time. I serve as the course director and teach about 40% of PHSL 6061, a Pharmacy Physiology course, and PHSL 6051, a Dental Physiology course. I also teach in PHSL 3061/3062w/5061, a Principles of Physiology course primarily for Majors and Biomedical Engineers. I also teach the last third of PHSL 6101, a course intended primarily for first year medical students and I teach some Pharmacology to second year medical students. I like to make guest appearances in many other biomedical courses, so you never know where I might pop up.

The Cellular and Integrative Physiology Graduate Program

In addition, I am the director of graduate studies for the Cellular and Integrative Physiology graduate Program where I help manage a special Masters Program intended for people in Biomedical Industry, as well as Ph.D. program that specializes in training PhD students with a previous medical background. Check out the Cellular and Integrative Physiology graduate program at http://physiology.med.umn.edu/grad/gc_iidx.htm

Stephen A. Katz can be reached at:

Stephen A. Katz, Ph.D.
Associate Professor of Physiology
Department of Physiology
University of Minnesota School of Medicine
321 Church St. S.E.
Minneapolis, MN 55455-0347

Phone: 612/625-9178
Fax: 612/625-5149
katzx001@umn.edu
Office 2-145 Jackson Hall (Map)