Annual Review of Physiology - Volume 73, 2011

This essay provides a summary of my professional activities. My interest in renal physiology started as a medical student in Vienna, when I became acquainted with Homer Smith's essays on kidney function. After moving to the United States in 1951, I was fortunate to be mentored by Robert Pitts, in whose Department of Physiology at Cornell Medical College in New York I was given early independence, intellectual stimulation, and the opportunity to pursue experiments on single renal tubules. The problem of how the nephron manages its myriad of transport functions has never lost its fascination for me, and I am profoundly grateful to the many colleagues at Cornell Medical College and at Yale University School of Medicine who shared my passion for the kidney.

The mature heart valves are made up of highly organized extracellular matrix (ECM) and valve interstitial cells (VICs) surrounded by an endothelial cell layer. The ECM of the valves is stratified into elastin-, proteoglycan-, and collagen-rich layers that confer distinct biomechanical properties to the leaflets and supporting structures. Signaling pathways have critical functions in primary valvulogenesis as well as the maintenance of valve structure and function over time. Animal models provide powerful tools to study valve development and disease processes. Valve disease is a significant public health problem, and increasing evidence implicates aberrant developmental mechanisms underlying pathogenesis. Further studies are necessary to determine regulatory pathway interactions underlying valve pathogenesis in order to generate new avenues for novel therapeutics.

The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post–myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling.

The morphological and functional design of gastrointestinal tracts of many vertebrates and invertebrates can be explained largely by the interaction between diet chemical constituents and principles of economic design, both of which are embodied in chemical reactor models of gut function. Natural selection seems to have led to the expression of digestive features that approximately match digestive capacities with dietary loads while exhibiting relatively modest excess. Mechanisms explaining differences in hydrolase activity between populations and species include gene copy number variations and single-nucleotide polymorphisms. In many animals, both transcriptional adjustment and posttranscriptional adjustment mediate phenotypic flexibility in the expression of intestinal hydrolases and transporters in response to dietary signals. Digestive performance of animals depends also on their gastrointestinal microbiome. The microbiome seems to be characterized by large beta diversity among hosts and by a common core metagenome and seems to differ flexibly among animals with different diets.

Drosophila melanogaster is a model genetic organism with an exceptional hypoxia tolerance relative to mammals. Forward genetic, microarray, and P-element manipulations and selection experiments have revealed multiple mechanisms of severe hypoxia tolerance, including RNA editing, downregulation of metabolism, and prevention of protein unfolding. Drosophila live in microbe-rich, semiliquid food in which hypoxia likely indicates deteriorating environments. Hypoxia reduces growth and size by multiple mechanisms, influencing larval feeding rates, protein synthesis, imaginal cell size, and control of molting. In moderate hypoxia, these effects appear to occur without ATP limitation and are instead mediated by signaling systems, including hypoxia-inducible factor and atypical guanyl cyclase sensing of oxygen, with downstream actions on behavior, anabolism, and the cell cycle. In hypoxia, flies develop smaller sizes, but size does not evolve, whereas in hyperoxia, flies evolve larger sizes without exhibiting developmental size plasticity, suggesting differential evolutionary responses to natural versus novel directions of oxygen change.

Late embryogenesis abundant (LEA) proteins are extremely hydrophilic proteins that were first identified in land plants. Intracellular accumulation is tightly correlated with acquisition of desiccation tolerance, and data support their capacity to stabilize other proteins and membranes during drying, especially in the presence of sugars like trehalose. Exciting reports now show that LEA proteins are not restricted to plants; multiple forms are expressed in desiccation-tolerant animals from at least four phyla. We evaluate here the expression, subcellular localization, biochemical properties, and potential functions of LEA proteins in animal species during water stress. LEA proteins are intrinsically unstructured in aqueous solution, but surprisingly, many assume their native conformation during drying. They are targeted to multiple cellular locations, including mitochondria, and evidence supports that LEA proteins stabilize vitrified sugar glasses thought to be important in the dried state. More in vivo experimentation will be necessary to fully unravel the multiple functional properties of these macromolecules during water stress.

Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.

Endometriosis is a common cause of pelvic pain and infertility, affecting ∼10% of reproductive-age women. Annual costs for medical and surgical care in the United States exceed $20 billion. The disorder is characterized by implants of endometrial tissue outside the uterine cavity. Endometriotic lesions induce a state of chronic peritoneal inflammation, accompanied by elevated prostaglandin, cytokine, and growth factor concentrations. The current therapy is surgical ablation of ectopic implants and hormones that block the hypothalamic-pituitary-ovarian axis, but these approaches are expensive, carry perioperative risks, or have unpleasant side effects of hypoestrogenism. Recent evidence indicates that ectopic endometriotic implants recruit their own unique neural and vascular supplies through neuroangiogenesis. It is believed that these nascent nerve fibers in endometriosis implants influence dorsal root neurons within the central nervous system, increasing pain perception in patients. We consider the mechanisms and therapeutic implications of neuroangiogenesis in these lesions and propose potential treatments for the control or elimination of endometriosis-associated pain.

Since its introduction as a genetic vertebrate model system approximately 30 years ago, the focus of zebrafish research has increasingly shifted to questions that are also relevant for human development and disease. Here, we review the potential of the zebrafish as a model for human endocrine systems. A recent review compared the functions of the different endocrine systems and glands in zebrafish with those in other vertebrates, including humans, coming to the conclusion that major aspects are conserved. Here, we present an updated overview of this rapidly growing field of zebrafish research, focusing on the hypothalamo-pituitary axis, which links the central nervous system with the endocrine systems, and on major processes that are under (neuro)endocrine control and are the subject of intensive current research in other endocrine model organisms, such as feeding circuits and energy homeostasis, sleep, stress, reproduction, osmoregulation, and calcium homeostasis. Finally, we summarize the strengths and weaknesses of zebrafish as a model for studying endocrine systems.

The mesenchymal elements of the intestinal lamina propria reviewed here are the myofibroblasts, fibroblasts, mural cells (pericytes) of the vasculature, bone marrow–derived stromal stem cells, smooth muscle of the muscularis mucosae, and smooth muscle surrounding the lymphatic lacteals. These cells share similar marker molecules, origins, and coordinated biological functions previously ascribed solely to subepithelial myofibroblasts. We review the functional anatomy of intestinal mesenchymal cells and describe what is known about their origin in the embryo and their replacement in adults. As part of their putative role in intestinal mucosal morphogenesis, we consider the intestinal stem cell niche. Lastly, we review emerging information about myofibroblasts as nonprofessional immune cells that may be important as an alarm system for the gut and as a participant in peripheral immune tolerance.

Increased blood cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Cholesterol homeostasis in the body is controlled mainly by endogenous synthesis, intestinal absorption, and hepatic excretion. Niemann-Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It functions as a sterol transporter to mediate intestinal cholesterol absorption and counterbalances hepatobiliary cholesterol excretion. NPC1L1 is the molecular target of ezetimibe, a potent cholesterol absorption inhibitor that is widely used in treating hypercholesterolemia. Recent findings suggest that NPC1L1 deficiency or ezetimibe treatment also prevents diet-induced hepatic steatosis and obesity in addition to reducing blood cholesterol. Future studies should focus on molecular mechanisms underlying NPC1L1-dependent cholesterol transport and elucidation of how a cholesterol transporter modulates the pathogenesis of metabolic diseases.

Na⁺ and Cl⁻ movement across the intestinal epithelium occurs by several interconnected mechanisms: (a) nutrient-coupled Na⁺ absorption, (b) electroneutral NaCl absorption, (c) electrogenic Cl⁻ secretion by CFTR, and (d) electrogenic Na⁺ absorption by ENaC. All these transport modes require a favorable electrochemical gradient maintained by the basolateral Na⁺/K⁺-ATPase, a Cl⁻ channel, and K⁺ channels. Electroneutral NaCl absorption is observed from the small intestine to the distal colon. This transport is mediated by apical Na⁺/H⁺ (NHE2/3) and Cl⁻/HCO3⁻ (Slc26a3/a6 and others) exchangers that provide the major route of NaCl absorption. Electroneutral NaCl absorption and Cl⁻ secretion by CFTR are oppositely regulated by the autonomic nerve system, the immune system, and the endocrine system via PKAα, PKCα, cGKII, and/or SGK1. This integrated regulation requires the formation of macromolecular complexes, which are mediated by the NHERF family of scaffold proteins and involve internalization of NHE3. Through use of knockout mice and human mutations, a more detailed understanding of the integrated as well as subtle regulation of electroneutral NaCl absorption by the mammalian intestine has emerged.

Tissue barriers that restrict passage of liquids, ions, and larger solutes are essential for the development of multicellular organisms. In simple organisms this allows distinct cell types to interface with the external environment. In more complex species, the diversity of cell types capable of forming barriers increases dramatically. Although the plasma membranes of these barrier-forming cells prevent flux of most hydrophilic solutes, the paracellular, or shunt, pathway between cells must also be sealed. This function is accomplished in vertebrates by the zonula occludens, or tight junction. The tight junction barrier is not absolute but is selectively permeable and is able to discriminate between solutes on the basis of size and charge. Many tight junction components have been identified over the past 20 years, and recent progress has provided new insights into the proteins and interactions that regulate structure and function. This review presents these data in a historical context and proposes an integrated model in which dynamic regulation of tight junction protein interactions determines barrier function.

Although the basic principles underlying the function of the peripheral auditory system have been known for many years, the molecules required for hearing have hitherto remained elusive. Genetic approaches have recently provided unparalleled molecular insight into how the hair bundle, the hair cell's mechanosensory organelle, forms and functions. We discuss how the proteins encoded by the Usher syndrome type 1 genes form molecular complexes required for hair-bundle development and for gating the mechanotransducer channel. We show how mouse models for nonsyndromic forms of deafness involving genes encoding Triobp and stereocilin reveal, respectively, the way stereocilia rootlets contribute to the hair bundle's mechanical properties and how the hair bundle produces suppressive masking, a property that contributes to speech intelligibility. Finally, we examine how mutations in the genes encoding α- and β-tectorin reveal multiple roles for the tectorial membrane, an extracellular matrix unique to the cochlea, in stimulating hair bundles.

The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.

NaCl absorption along the nephron is regulated not just by humoral factors but also by factors that do not circulate or act on the cells where they are produced. Generally, nitric oxide (NO) inhibits NaCl absorption along the nephron. However, the effects of NO in the proximal tubule are controversial and may be biphasic. Similarly, the effects of endothelin on proximal tubule transport are biphasic. In more distal segments, endothelin inhibits NaCl absorption and may be mediated by NO. Adenosine triphosphate (ATP) inhibits sodium bicarbonate absorption in the proximal tubule, NaCl absorption in thick ascending limbs via NO, and water reabsorption in collecting ducts. Defects in the effects of NO, endothelin, and ATP increase blood pressure, especially in a NaCl-sensitive manner. In diabetes, disruption of NO-induced inhibition of transport may contribute to increased blood pressure and renal damage. However, our understanding of how NO, endothelin, and ATP work, and of their role in pathology, is rudimentary at best.

In the adult organism, systemically circulating renin almost exclusively originates from the juxtaglomerular cells in the afferent arterioles of the kidneys. These cells share similarities with pericytes and myofibro-blasts. They store renin in a vesicular network and granules and release it in a regulated fashion. The release mode of renin is not understood; in particular, the involvement of SNARE proteins is unknown. Renin release is acutely increased via the cAMP signaling pathway, which is triggered mainly by catecholamines and other Gs-coupled agonists, and is inhibited by calcium-related pathways that are commonly activated by vasoconstrictors. Renin release from juxtaglomerular cells is directly modulated in an inverse fashion by the blood pressure inside the afferent arterioles and by the chloride content in the tubule fluid at the macula densa segment of the distal tubule. Renin release is stimulated by nitric oxide and by prostanoids released by neighboring endothelial and macula densa cells. Steady-state renin concentrations in the plasma are determined essentially by the number of renin-producing cells in the afferent arterioles, which changes in parallel with challenges to the renin-angiotensin-aldosterone system.

Epithelia, the most abundant cell type, differentiate to protoepithelia from stem cells by developing apical and basolateral membrane domains and form sheets of cells connected by junctions. Following this differentiation step, the cells undergo a second step (terminal differentiation), during which they acquire a mature phenotype, which unlike the protoepithelial one is tissue and organ specific. An extracellular matrix (ECM) protein termed hensin (DMBT1) mediates this differentiation step in the kidney intercalated cells. Although hensin is secreted as a soluble monomer, it requires polymerization and deposition in the ECM to become active. The polymerization step is mediated by the activation of inside-out signaling by integrins and by the secretion of two proteins: cypA (a cis-trans prolyl isomerase) and galectin 3.

Lung epithelial cells have emerged as a frequent target of injury, a driver of normal repair, and a key element in the pathobiology of fibrotic lung diseases. An important aspect of epithelial cells is their capacity to respond to microenvironmental cues by undergoing epithelial-mesenchymal transition (EMT). EMT is not simply widespread conversion of epithelial cells to fibroblasts but a graded response whereby epithelial cells reversibly acquire mesenchymal features and enhanced capacity for mesenchymal cross-talk. Recent studies elucidate distinct integrin-sensing systems that coordinate activity of TGFβ1, a critical signaling element regulating EMT, with the presence of proinflammatory signals and cell injury. Repeated injury superimposes persistent inflammation and hypoxia onto these highly regulated repair pathways, potentially overwhelming orderly repair and creating sustained fibrogenesis. Understanding specific signaling mechanisms driving the mesenchymal response to TGFβ1 may reveal therapeutics to attenuate fibrogenesis yet preserve the important homeostatic functions of TGFβ1.