Cellular and Molecular Biology of the Renin-Angiotensin System provides the first review and update of the state-of-the-art cellular and molecular aspects of the renin-angiotensin system. The book presents detailed analyses from world experts on each component of this system, including future directions. Topics range from angiotensin II receptor subtypes to processing of renin to the use of transgenic animal models for studying the role of this system in hypertension. Cellular and Molecular Biology of the Renin-Angiotensin System is essential reading for physiologists of the renin-angiotensin system, endocrinologists, cardiovascular specialists, renal physiologists, and neurobiologists.

An essential element in the development and functional integrity of all organisms is intercellular communication. This is achieved by the secretion of soluble messenger molecules which subsequently interact with receptor-effector pathways in the responsive cells. Hormones are traditionally defined as chemical messengers synthesized by endocrine glands. Unlike hormones produced by endocrine glands, growth factors are hormone-related substances produced by many tissues and play an important role in controlling growth and development. While the exact physiological roles of growth factors have yet to be elucidated, they play important roles in the regulation of cellular proliferation and/or differentiation during ontogenesis, growth and differentiation. During recent years there has been a substantial increase in research related to peptide growth factors, their receptors, and modes of action. With the discovery and characterization of numerous growth factors, it became clear that these growth factors had multiple features in common with classic hormones as well as with oncogenes. Furthermore, there are distinct families of growth factors based either on structural or functional similarities.

Recent progress in recombinant DNA technology and the availability of a number of nonpeptide subtype-specific receptor antagonists and of specific antibodies to components of prorenin-renin-angiotensin system (PRAS) have led to rapid advances in the under standing of the multifaceted role of angiotensin II, classically known as a peptide hormone of cardiovascular homeostasis. Accumulating evidence sug responsible for the regulation gests that, in addition to its role in salt and water metabolism, PRAS may control other physiological functions including neurosecretion, cellular proliferation, hypertrophy and/or differentiation, angiogenesis and gonadal function. At the same time, it is becoming evident that the specialized functions of endocrine glands are not only regulated by trophic hormones but also by locally produced paracrine/autocrine factors. The concept is emerging that tissue PRAS is one such locally active regulatory system. With more and more reproductive and endocrine organs being added to the list of tissues that contain a local tissue PRAS, questions are being raised by the reproductive biologists and endocrinologists as to the role of such systems in the tissues of their interest. On the other hand, the cardiovascular and renovascular physiologists are wondering about the relevance of PRAS in various peripheral tissues compared to those of the classical cardiovascular organs. It appeared, therefore, that the time was ripe for a meeting to consider a merger of interest in these two important but heretofore distinct areas of physiology."

Scientific advances over the past two decades have afforded unprecedented oppor tunities to understand the structure and function of receptors, receptor-ligand interactions, and receptor signaling. The extent ofprogress in this area is underscored by the recent Nobel Prize for Medicine and Physiology to Alfred Gilman and Martin Rodbell, both of whose work in understanding receptorlG-protein interactions has redefined the way in which we think of how hormones and neurochemicals exert their activity on cellular function. This book is replete with examples of current research approaches to help us better understand the cellular roles in which the renin-angiotensin system and the angiotensin receptors participate. Clearly, defining the structure of angiotensin receptor subtypes is an important first step in cJarifying the mechanisms by which these receptors take part in cellular function. However, the chapters within this book range far beyond structural studies and encompass research on tissue specific expression of the angiotensin receptor subtypes, the genetic regulation ofthese receptors, and the unique function ofvarious angiotensin subtypes in different organ systems, such as the brain, the reproductive system, adipose tissue, the heart, and the kidneys."

The study of the insulin-like growth factor (IGF) family has become an exciting area of investigation. Initially, this family consisted of ligands (insulin, IGF-I and IGF-m and receptors (the insulin receptor, the type I or IGF-I receptor and the type II or IGF-IYM-6-P receptor). Subsequently, it was discovered that six specific binding proteips (lGFBPs 1-6) playa major role in the actions of this growth factor family. In addition, there are now more potential receptors when one considers the possible roles of the insulin-receptor related receptor (IRR) and hybrid receptor dimers composed of insulin and IGF-I receptor (half-receptors). Another important aspect of this area of research is the realization that the IGFs are not only essential for normal growth and development but, in addition play an important role in the normal specialized function(s) of all tissues of the body, including the nervous system, skeleton, reproductive system, kidney, and the immune system, to name but a few. The development of recombi tant human IGF-I for clinical testing has been a major breakthrough for investigators. Potential uses include wound healing, reversal of catabolic states, diabetes, bone remodeling, recovery from acute renal failure and many others. will determine both its use and its potential hazards.

This volume addresses a fundamental puzzle in biology and medicine, namely, how does tissue develop, repair and replace itself. The answer appears to lie in growth factors and their regulation. To thrive and survive we need growth factors and this book concentrates on two factors that are related to growth hormone. Growth hormone does not act directly on all tissues, but mediates many of its actions through the release of insulin-like growth factors from the liver. The growth factors were originally called somatomedins by McConaghey and Sledge (1), who discovered that they mediated growth-like effects of growth hormone. However, the factors were purified on the basis of their insulinomimetic actions on fat and muscle and it is their relationship to the insulin family of pep tides that now gives them their name (2,3) of insulin-like growth factors (IGFs). They mediate the actions of. growth hormone on the proteoglycan synthesis of cartilage and produce mitogenic effects in fibroblast cultures.

Recognized scientists and clinicians from around the world discuss the most recent molecular approaches to understanding the cardiovascular system in both health and disease. The authors focus on all components of the system, including blood vessels, heart, kidneys, and the brain, and cover disease states ranging from vascular and cardiac dysfunction to stroke and hypertension. The methods described for identifying the genes that cause susceptibility to cardiovascular diseases emphasize the possibility of discovering new drug targets. Authoritative and ground-breaking, Cardiovascular Genomics offers an unprecedented examination of both the cutting-edge scientific approaches now possible and the results obtained from them in the new science of cardiovascular genomics.

Recent progress in recombinant DNA technology and the availability of a number of nonpeptide subtype-specific receptor antagonists and of specific antibodies to components of prorenin-renin-angiotensin system (PRAS) have led to rapid advances in the under standing of the multifaceted role of angiotensin II, classically known as a peptide hormone of cardiovascular homeostasis. Accumulating evidence sug responsible for the regulation gests that, in addition to its role in salt and water metabolism, PRAS may control other physiological functions including neurosecretion, cellular proliferation, hypertrophy and/or differentiation, angiogenesis and gonadal function. At the same time, it is becoming evident that the specialized functions of endocrine glands are not only regulated by trophic hormones but also by locally produced paracrine/autocrine factors. The concept is emerging that tissue PRAS is one such locally active regulatory system. With more and more reproductive and endocrine organs being added to the list of tissues that contain a local tissue PRAS, questions are being raised by the reproductive biologists and endocrinologists as to the role of such systems in the tissues of their interest. On the other hand, the cardiovascular and renovascular physiologists are wondering about the relevance of PRAS in various peripheral tissues compared to those of the classical cardiovascular organs. It appeared, therefore, that the time was ripe for a meeting to consider a merger of interest in these two important but heretofore distinct areas of physiology."

Structure, Expression, and Regulation of the IGF-I Gene.- Differential Regulation of IGF-I Leader Exon Transcription.- Insulin and IGF-I Analogs: Novel Approaches to Improved Insulin Pharmacokinetics.- Analysis of the Interaction of Igf-I Analogs with the IGF-I Receptor and IGF Binding Proteins.- Synthesis and Characterization of IGF-II Analogs: Applications in the Evaluation of IGF Receptor Function and IGF-Independent Actions of IGFBPS.- Towards Identification of a Binding Site on Insulinlike Growth Factor-II for IGF-Binding Proteins.- Transcriptional and Post-Transcriptional Regulation of the Human IGF-II Gene Expression.- Significant Species Differences in Local IGF-I and -II Gene Expression.- Transcriptional Regulation of the Insulin Receptor Gene Promoter.- The Regulation of IGF-I Receptor Gene Expression by Positive and Negative Zinc-Finger Transcription Factors.- Cell Cycle Control by the IGF-1 Receptor and Its Ligands.- The Insulin Receptor Family.- IRR: a Novel Member of the Insulin Receptor Family.- Molecular Properties of Insulin/IGF-1 Hybrid Receptors.- Immunological Studies of Type I IGF Receptors and Insulin Receptors: Haracterisation of Hybrid and Atypical Receptor Subtypes.- Insulin like Growth Factor 1 Receptor Signal Transduction to the Nucleus.- Molecular Cloning of pp120/ ECTO-ATPase, An Endogenous Substrate of the Insulin Receptor Kinase.- The Insulin-like Growth Factor-II/mannose-6-Phosphate Receptor: Structure, Function and Differential Expression.- Parental Imprinting of the Genes for IGF-II and Its Receptor.- Multihormonal Regulation of IGFBP-1 Promoter Activity.- Insulin-like Growth Factor Binding Protein-1: Identification, Purification, and Regulation in Fetal and Adult Life.- Rapid Regulation of Insulin-like Growth Factor Binding Protein-1 Transcription by Insulin In Vito and In Vivo.- IGF Binding Protein-3 and the ACID-labile Subunit: Formation of the Ternary Complex In Vitro and In Vivo.- Role of Post Translational Modifications in Modifying the Biologic Activity of Insulin like Growth Factor Binding Proteins.- Cellular Actions of Insulin-like Growth Factor Binding Protein-3.- Gene Expression of the IGF Binding Proteins during Post-Implantation Embryogenesis of the Mouse: Comparison with the Expression of IGF-I and -II and Their Receptors in Rodent and Human.- Hormonal Regulation of Insulin-like Growth Factor Binding Protein-1 Expression and the Development of Transgenic Mouse Models to Study IGFBP-1 Function.- Limited Proteolysis of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3): A Physiological Mechanism in the Regulation of IGF Bioavailability.- Effects of Insulin-like Growth Factor 1 (IGF-I) Administrations on Serum IGF Binding Proteins (IGFBPS) in Patients with Growth Hormone Deficiency.- Metabolic Effects of rhIGF-1 in Normal Human Subjects.- IGFS and Muscle Differentiation.- IGF-II in the Pathogenesis of Rhabdomyosarcoma: a Prototype of IGFS Involvement in Human Tumorigenesis.- The Physiology and Pathophysiology of IGF-I in the Kidney.- Regulation of IGFBP-4 and -5 Expression in Rat Granulosa Cells.- Insulin-like Growth Factor (IGF) Binding Protein-1 Is an Antigonadotropin: Evidence that Optimal Follicle-Stimulating Hormone Action in Ovarian Granulosa Cells Is Contingent upon Amplification by Endogenously-Derived IGFS.- Insulin-like Growth Factor-I and Insulin-like Growth Factor Binding Proteins in the Zucker Fatty Rat: a case for Differential Tissue Regulation.- Characterization of the IGF Regulatory System in Bone.- Regulation of IGF Activity in Bone.

An essential element in the development and functional integrity of all organisms is intercellular communication. This is achieved by the secretion of soluble messenger molecules which subsequently interact with receptor-effector pathways in the responsive cells. Hormones are traditionally defined as chemical messengers synthesized by endocrine glands. Unlike hormones produced by endocrine glands, growth factors are hormone-related substances produced by many tissues and play an important role in controlling growth and development. While the exact physiological roles of growth factors have yet to be elucidated, they play important roles in the regulation of cellular proliferation and/or differentiation during ontogenesis, growth and differentiation. During recent years there has been a substantial increase in research related to peptide growth factors, their receptors, and modes of action. With the discovery and characterization of numerous growth factors, it became clear that these growth factors had multiple features in common with classic hormones as well as with oncogenes. Furthermore, there are distinct families of growth factors based either on structural or functional similarities.