Function of Renal Nerves in Kidney Physiology and Pathophysiology
Annu Rev Physiol. 2021 Feb 10;83:429-450. doi: 10.1146/annurev-physiol-031620-091656.ABSTRACTRenal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation ...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: John W Osborn Roman Tyshynsky Lucy Vulchanova Source Type: research

Uromodulin: Roles in Health and Disease
Annu Rev Physiol. 2021 Feb 10;83:477-501. doi: 10.1146/annurev-physiol-031620-092817.ABSTRACTUromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago, uromodulin has gained the spotlight in recent years, since the discovery that mutations in its encoding gene UMOD cause a renal Mendelian disease (autosomal dominant tubulointerstitial kidney disease) and that common polymorphisms are associated with multifactorial disorders, such as chronic kidney disease, hypertension, and cardiovascular diseases. Moreover, variations i...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: C éline Schaeffer Olivier Devuyst Luca Rampoldi Source Type: research

Metabolism in Pulmonary Hypertension
Annu Rev Physiol. 2021 Feb 10;83:551-576. doi: 10.1146/annurev-physiol-031620-123956.ABSTRACTPulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics are increasingly recognized as universal hallmarks of PAH, as metabolic abnormalities are identified in lungs and hearts of patients, animal models of the disease, and cells derived from lungs of patients. Mitochondria are the primary organelle critically mediating the complex and integrative metabolic pathways in bioenergetics, biosynthetic pathways, and cell signa...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: Weiling Xu Allison J Janocha Serpil C Erzurum Source Type: research

Cellular Heterogeneity in Adipose Tissues
Annu Rev Physiol. 2021 Feb 10;83:257-278. doi: 10.1146/annurev-physiol-031620-095446.ABSTRACTAdipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues. In addition to mature adipocytes and their progenitors, these include end...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: Silvia Corvera Source Type: research

Function of Renal Nerves in Kidney Physiology and Pathophysiology.
Abstract Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater ...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: Osborn JW, Tyshynsky R, Vulchanova L Tags: Annu Rev Physiol Source Type: research

Uromodulin: Roles in Health and Disease.
Abstract Uromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago, uromodulin has gained the spotlight in recent years, since the discovery that mutations in its encoding gene UMOD cause a renal Mendelian disease (autosomal dominant tubulointerstitial kidney disease) and that common polymorphisms are associated with multifactorial disorders, such as chronic kidney disease, hypertension, and cardiovascular diseases. Moreover, variations in uromodulin levels in urine and/or blood reflect kidney functioning mass a...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: Schaeffer C, Devuyst O, Rampoldi L Tags: Annu Rev Physiol Source Type: research

Metabolism in Pulmonary Hypertension.
Abstract Pulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics are increasingly recognized as universal hallmarks of PAH, as metabolic abnormalities are identified in lungs and hearts of patients, animal models of the disease, and cells derived from lungs of patients. Mitochondria are the primary organelle critically mediating the complex and integrative metabolic pathways in bioenergetics, biosynthetic pathways, and cell signaling. Here, we review the alterations in metabolic pathways that are linked...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: Xu W, Janocha AJ, Erzurum SC Tags: Annu Rev Physiol Source Type: research

Cellular Heterogeneity in Adipose Tissues.
Abstract Adipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues. In addition to mature adipocytes and their progenitors, these include endothelial and various immune cell types that together orchestrate adipose ti...
Source: Annual Review of Physiology - February 10, 2021 Category: Physiology Authors: Corvera S Tags: Annu Rev Physiol Source Type: research

Epigenetic Signatures and Plasticity of Intestinal and Other Stem Cells.
Abstract The cardinal properties of adult tissue stem cells are self-renewal and the ability to generate diverse resident cell types. The daily losses of terminally differentiated intestinal, skin, and blood cells require "professional" stem cells to produce replacements. This occurs by continuous expansion of stem cells and their immediate progeny, followed by coordinated activation of divergent transcriptional programs to generate stable cells with diverse functions. Other tissues turn over slowly, if at all, and vary widely in strategies for facultative stem cell activity or interconversion among matu...
Source: Annual Review of Physiology - November 24, 2020 Category: Physiology Authors: Saxena M, Shivdasani RA Tags: Annu Rev Physiol Source Type: research

Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation.
Abstract Aldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance of plasma membrane conductances in determining the activation-state of zona glomerulosa (zG) cells. Electrophysiological recordings describe an electrically quiescent behavior for dispersed zG cells. Yet, emerging data indicate that in native rosette structures in situ, zG cells are electrically excitable, generating slow periodic voltage spikes and coordinated bursts of Ca2+ oscillations. We revisit data...
Source: Annual Review of Physiology - November 11, 2020 Category: Physiology Authors: Barrett PQ, Guagliardo NA, Bayliss DA Tags: Annu Rev Physiol Source Type: research

The  Remarkable Cardiovascular System of Giraffes.
The Remarkable Cardiovascular System of Giraffes. Annu Rev Physiol. 2020 Nov 09;: Authors: Aalkjær C, Wang T Abstract Gravity affects the physiology of many animals, and the effect is, for good reason, most pronounced in tall species. The physiology-in particular, cardiovascular function-of giraffes has therefore captivated the interest of physiologists for centuries. Several studies document high mean arterial blood pressure of giraffes of about 200 mm Hg. This appears necessary to establish a cerebral perfusion pressure on the order of 100 mm Hg at the cranial end of the carotid arte...
Source: Annual Review of Physiology - November 9, 2020 Category: Physiology Authors: Aalkjær C, Wang T Tags: Annu Rev Physiol Source Type: research

Uterine Excitability and Ion Channels and Their Changes with Gestation and Hormonal Environment.
Abstract We address advances in the understanding of myometrial physiology, focusing on excitation and the effects of gestation on ion channels and their relevance to labor. This review moves through pioneering studies to exciting new findings. We begin with the myometrium and its myocytes and describe how excitation might initiate and spread in this myogenic smooth muscle. We then review each of the ion channels in the myometrium: L- and T-type Ca2+ channels, KATP (Kir6) channels, voltage-dependent K channels (Kv4, Kv7, and Kv11), twin-pore domain K channels (TASK, TREK), inward rectifier Kir7.1, Ca2+-activated K...
Source: Annual Review of Physiology - November 6, 2020 Category: Physiology Authors: Wray S, Arrowsmith S Tags: Annu Rev Physiol Source Type: research

Brown Adipose Tissue: A Metabolic Regulator in a Hypothalamic Cross Talk?
Abstract Since the discovery of functionally competent, energy-consuming brown adipose tissue (BAT) in adult humans, much effort has been devoted to exploring this tissue as a means for increasing energy expenditure to counteract obesity. However, despite promising effects on metabolic rate and insulin sensitivity, no convincing evidence for weight-loss effects of cold-activated human BAT exist to date. Indeed, increasing energy expenditure would naturally induce compensatory feedback mechanisms to defend body weight. Interestingly, BAT is regulated by multiple interactions with the hypothalamus from regions overl...
Source: Annual Review of Physiology - November 6, 2020 Category: Physiology Authors: Henningsen JB, Scheele C Tags: Annu Rev Physiol Source Type: research

Ceramides in Metabolism: Key Lipotoxic Players.
Abstract The global prevalence of metabolic diseases such as type 2 diabetes mellitus, steatohepatitis, myocardial infarction, and stroke has increased dramatically over the past two decades. These obesity-fueled disorders result, in part, from the aberrant accumulation of harmful lipid metabolites in tissues not suited for lipid storage (e.g., the liver, vasculature, heart, and pancreatic beta-cells). Among the numerous lipid subtypes that accumulate, sphingolipids such as ceramides are particularly impactful, as they elicit the selective insulin resistance, dyslipidemia, and ultimately cell death that underlie n...
Source: Annual Review of Physiology - November 6, 2020 Category: Physiology Authors: Chaurasia B, Summers SA Tags: Annu Rev Physiol Source Type: research

The ABCs of Sterol Transport.
Abstract Cholesterol homeostasis and trafficking are critical to the maintenance of the asymmetric plasma membrane of eukaryotic cells. Disruption or dysfunction of cholesterol trafficking leads to numerous human diseases. ATP-binding cassette (ABC) transporters play several critical roles in this process, and mutations in these sterol transporters lead to disorders such as Tangiers disease and sitosterolemia. Biochemical and structural information on ABC sterol transporters is beginning to emerge, with published structures of ABCA1 and ABCG5/G8; these two proteins function in the reverse cholesterol transport pat...
Source: Annual Review of Physiology - November 3, 2020 Category: Physiology Authors: Plummer AM, Culbertson AT, Liao M Tags: Annu Rev Physiol Source Type: research

Regulation of Mitochondrial Ca2+ Uptake.
Abstract Mitochondria are responsible for ATP production but are also known as regulators of cell death, and mitochondrial matrix Ca2+ is a key modulator of both ATP production and cell death. Although mitochondrial Ca2+ uptake and efflux have been studied for over 50 years, it is only in the past decade that the proteins responsible for mitochondrial Ca2+ uptake and efflux have been identified. The identification of the mitochondrial Ca2+ uniporter (MCU) led to an explosion of studies identifying regulators of the MCU. The levels of these regulators vary in a tissue- and disease-specific manner, providing new ins...
Source: Annual Review of Physiology - November 3, 2020 Category: Physiology Authors: Murphy E, Steenbergen C Tags: Annu Rev Physiol Source Type: research

Sestrins in Physiological Stress Responses.
Abstract Sestrins are a family of proteins that respond to a variety of environmental stresses, including genotoxic, oxidative, and nutritional stresses. Sestrins affect multiple signaling pathways: AMP-activated protein kinase, mammalian target of rapamycin complexes, insulin-AKT, and redox signaling pathways. By regulating these pathways, Sestrins are thought to help adapt to stressful environments and subsequently restore cell and tissue homeostasis. In this review, we describe how Sestrins mediate physiological stress responses in the context of nutritional and chemical stresses (liver), physical movement and ...
Source: Annual Review of Physiology - October 28, 2020 Category: Physiology Authors: Kim M, Kowalsky AH, Lee JH Tags: Annu Rev Physiol Source Type: research

Voltage-Gated Calcium Channels in Nonexcitable Tissues.
Abstract The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. Previous studies in cells and animal models had suggested that several voltage-gated Ca2+ channels (VGCCs) regulated critical signaling events in various cell types that are not expected to support action potential, but definitive data were lacking. VGCCs occupy a special position among ion channels, uniquely able to translate membrane excitability into th...
Source: Annual Review of Physiology - October 26, 2020 Category: Physiology Authors: Pitt GS, Matsui M, Cao C Tags: Annu Rev Physiol Source Type: research

Temperature Sensation: From Molecular Thermosensors to Neural Circuits and Coding Principles.
Abstract Temperature is a universal cue and regulates many essential processes ranging from enzymatic reactions to species migration. Due to the profound impact of temperature on physiology and behavior, animals and humans have evolved sophisticated mechanisms to detect temperature changes. Studies from animal models, such as mouse, Drosophila, and C. elegans, have revealed many exciting principles of thermosensation. For example, conserved molecular thermosensors, including thermosensitive channels and receptors, act as the initial detectors of temperature changes across taxa. Additionally, thermosensory neurons ...
Source: Annual Review of Physiology - October 21, 2020 Category: Physiology Authors: Xiao R, Xu XZS Tags: Annu Rev Physiol Source Type: research

Renal Denervation to Treat Heart Failure.
Abstract Heart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these ...
Source: Annual Review of Physiology - October 19, 2020 Category: Physiology Authors: Sharp Iii TE, Lefer DJ Tags: Annu Rev Physiol Source Type: research

Epithelial Stem and Progenitor Cells in Lung Repair and Regeneration.
Abstract The mammalian lung epithelium is composed of a wide array of specialized cells that have adapted to survive environmental exposure and perform the tasks necessary for respiration. Although the majority of these cells are remarkably quiescent during adult lung homeostasis, a growing body of literature has demonstrated the capacity of these epithelial lineages to proliferate in response to injury and regenerate lost or damaged cells. In this review, we focus on the regionally distinct lung epithelial cell types that contribute to repair after injury, and we address current controversies regarding whether el...
Source: Annual Review of Physiology - October 19, 2020 Category: Physiology Authors: Alysandratos KD, Herriges MJ, Kotton DN Tags: Annu Rev Physiol Source Type: research

Dynamics of Atrial Fibrillation Mechanisms and Comorbidities.
Abstract Atrial fibrillation (AF) contributes to morbidity and mortality of millions of individuals. Its molecular, cellular, neurohumoral, and hemodynamic pathophysiological mechanisms are complex, and there is increasing awareness that a wide range of comorbidities can contribute to AF-promoting atrial remodeling. Moreover, recent research has highlighted that AF risk is not constant and that the temporal variation in concomitant conditions contributes to the complexity of AF dynamics. In this review, we provide an overview of fundamental AF mechanisms related to established and emerging comorbidities or risk fa...
Source: Annual Review of Physiology - October 16, 2020 Category: Physiology Authors: Heijman J, Linz D, Schotten U Tags: Annu Rev Physiol Source Type: research

Cardiac Regeneration: New Hope for an Old Dream.
Abstract The regenerative capacity of the heart has long fascinated scientists. In contrast to other organs such as liver, skin, and skeletal muscle, the heart possesses only a minimal regenerative capacity. It lacks a progenitor cell population, and cardiomyocytes exit the cell cycle shortly after birth and do not re-enter after injury. Thus, any loss of cardiomyocytes is essentially irreversible and can lead to or exaggerate heart failure, which represents a major public health problem. New therapeutic options are urgently needed, but regenerative therapies have remained an unfulfilled promise in cardiovascular ...
Source: Annual Review of Physiology - October 16, 2020 Category: Physiology Authors: Weinberger F, Eschenhagen T Tags: Annu Rev Physiol Source Type: research

Regulation of Hemogenic Endothelial Cell Development and Function.
Abstract Embryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for establishment and maintenance of the adult blood system. This process requires the specification of a subset of vascular endothelial cells to become blood-forming, or hemogenic, and the subsequent endothelial-to-hematopoietic transition to generate HSPCs therefrom. The mechanisms that regulate these processes are under intensive investigation, as their recapitulation in vitro from human pluripotent stem cells has the potential to generate autologous HSPCs for clinical applications. In this review, we...
Source: Annual Review of Physiology - October 9, 2020 Category: Physiology Authors: Wu Y, Hirschi KK Tags: Annu Rev Physiol Source Type: research

Hedgehog Signaling in Intestinal Development and Homeostasis.
Abstract The hedgehog (Hh) signaling pathway plays several diverse regulatory and patterning roles during organogenesis of the intestine and in the regulation of adult intestinal homeostasis. In the embryo, fetus, and adult, intestinal Hh signaling is paracrine: Hh ligands are expressed in the endodermally derived epithelium, while signal transduction is confined to the mesenchymal compartment, where at least a dozen distinct cell types are capable of responding to Hh signals. Epithelial Hh ligands not only regulate a variety of mesenchymal cell behaviors, but they also direct these mesenchymal cells to secrete ad...
Source: Annual Review of Physiology - October 9, 2020 Category: Physiology Authors: Walton KD, Gumucio DL Tags: Annu Rev Physiol Source Type: research

Cardiac Fibroblast Diversity.
Abstract Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of thes...
Source: Annual Review of Physiology - February 9, 2020 Category: Physiology Authors: Tallquist MD Tags: Annu Rev Physiol Source Type: research

The Osteocyte: New Insights.
Abstract Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL/OPG axis...
Source: Annual Review of Physiology - February 9, 2020 Category: Physiology Authors: Robling AG, Bonewald LF Tags: Annu Rev Physiol Source Type: research

Cardiac Pacemaker Activity and Aging.
Abstract A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which...
Source: Annual Review of Physiology - November 21, 2019 Category: Physiology Authors: Peters CH, Sharpe EJ, Proenza C Tags: Annu Rev Physiol Source Type: research

Regulation and Effects of FGF23 in Chronic Kidney Disease.
Abstract Chronic kidney disease (CKD) is a global health epidemic that accelerates cardiovascular disease, increases risk of infection, and causes anemia and bone disease, among other complications that collectively increase risk of premature death. Alterations in calcium and phosphate homeostasis have long been considered nontraditional risk factors for many of the most morbid outcomes of CKD. The discovery of fibroblast growth factor 23 (FGF23), which revolutionized the diagnosis and treatment of rare hereditary disorders of FGF23 excess that cause hypophosphatemic rickets, has also driven major paradigm shifts ...
Source: Annual Review of Physiology - November 18, 2019 Category: Physiology Authors: Musgrove J, Wolf M Tags: Annu Rev Physiol Source Type: research

Gestational Exposure to Common Endocrine Disrupting Chemicals and Their Impact on Neurodevelopment and Behavior.
Abstract Endocrine disrupting chemicals are common in our environment and act on hormone systems and signaling pathways to alter physiological homeostasis. Gestational exposure can disrupt developmental programs, permanently altering tissues with impacts lasting into adulthood. The brain is a critical target for developmental endocrine disruption, resulting in altered neuroendocrine control of hormonal signaling, altered neurotransmitter control of nervous system function, and fundamental changes in behaviors such as learning, memory, and social interactions. Human cohort studies reveal correlations between matern...
Source: Annual Review of Physiology - November 17, 2019 Category: Physiology Authors: Nesan D, Kurrasch DM Tags: Annu Rev Physiol Source Type: research

Aging and Lung Disease.
Abstract People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging population rapidly grows, it is essential to examine how alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and systemic immune cells contribute to a higher risk of inc...
Source: Annual Review of Physiology - November 14, 2019 Category: Physiology Authors: Jung Cho S, Stout-Delgado HW Tags: Annu Rev Physiol Source Type: research

IP3 Receptor Plasticity Underlying Diverse Functions.
Abstract In the body, extracellular stimuli produce inositol 1,4,5-trisphosphate (IP3), an intracellular chemical signal that binds to the IP3 receptor (IP3R) to release calcium ions (Ca2+) from the endoplasmic reticulum. In the past 40 years, the wide-ranging functions mediated by IP3R and its genetic defects causing a variety of disorders have been unveiled. Recent cryo-electron microscopy and X-ray crystallography have resolved IP3R structures and begun to integrate with concurrent functional studies, which can explicate IP3-dependent opening of Ca2+-conducting gates placed ∼90 Å away from IP3-binding...
Source: Annual Review of Physiology - November 14, 2019 Category: Physiology Authors: Hamada K, Mikoshiba K Tags: Annu Rev Physiol Source Type: research

Genetics of COPD.
Abstract Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with COPD-related phenotypes, such as quantitative emphysema measures, have been found. Identifying the functional variants and key genes within these association regions remains a major challenge. However, newly ide...
Source: Annual Review of Physiology - November 14, 2019 Category: Physiology Authors: Silverman EK Tags: Annu Rev Physiol Source Type: research

The Acidic Tumor Microenvironment as a Driver of Cancer.
Abstract Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex e...
Source: Annual Review of Physiology - November 14, 2019 Category: Physiology Authors: Boedtkjer E, Pedersen SF Tags: Annu Rev Physiol Source Type: research

APOL1 and Kidney Disease: From Genetics to Biology.
Abstract Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic Trypanosomes that cause African sleeping sickness. We consider the genetic evidence supporting the association between APOL1 and kidney disease across the range of clinical phenotypes in the APOL1 nephropa...
Source: Annual Review of Physiology - November 10, 2019 Category: Physiology Authors: Friedman DJ, Pollak MR Tags: Annu Rev Physiol Source Type: research

Marrow Adipocytes: Origin, Structure, and Function.
Abstract The skeleton harbors an array of lineage cells that have an essential role in whole body homeostasis. Adipocytes start the colonization of marrow space early in postnatal life, expanding progressively and influencing other components of the bone marrow through paracrine signaling. In this unique, closed, and hypoxic environment close to the endosteal surface and adjacent to the microvascular space the marrow adipocyte can store or provide energy, secrete adipokines, and target neighboring bone cells. Adipocyte progenitors can also migrate from the bone marrow to populate white adipose tissue, a process th...
Source: Annual Review of Physiology - November 7, 2019 Category: Physiology Authors: de Paula FJA, Rosen CJ Tags: Annu Rev Physiol Source Type: research

New Approaches to Target Inflammation in Heart Failure: Harnessing Insights from Studies of Immune Cell Diversity.
Abstract Despite mounting evidence implicating inflammation in cardiovascular diseases, attempts at clinical translation have shown mixed results. Recent preclinical studies have reenergized this field and provided new insights into how to favorably modulate cardiac macrophage function in the context of acute myocardial injury and chronic disease. In this review, we discuss the origins and roles of cardiac macrophage populations in the steady-state and diseased heart, focusing on the human heart and mouse models of ischemia, hypertensive heart disease, and aortic stenosis. Specific attention is given to delineatin...
Source: Annual Review of Physiology - October 27, 2019 Category: Physiology Authors: Rhee AJ, Lavine KJ Tags: Annu Rev Physiol Source Type: research

Autophagy in Kidney Disease.
Abstract Autophagy is a cellular homeostatic program for the turnover of cellular organelles and proteins, in which double-membraned vesicles (autophagosomes) sequester cytoplasmic cargos, which are subsequently delivered to the lysosome for degradation. Emerging evidence implicates autophagy as an important modulator of human disease. Macroautophagy and selective autophagy (e.g., mitophagy, aggrephagy) can influence cellular processes, including cell death, inflammation, and immune responses, and thereby exert both adaptive and maladaptive roles in disease pathogenesis. Autophagy has been implicated in acute kidn...
Source: Annual Review of Physiology - October 21, 2019 Category: Physiology Authors: Choi ME Tags: Annu Rev Physiol Source Type: research

Diurnal Regulation of Renal Electrolyte Excretion: The Role of Paracrine Factors.
Abstract Many physiological processes, including most kidney-related functions, follow specific rhythms tied to a 24-h cycle. This is largely because circadian genes operate in virtually every cell type in the body. In addition, many noncanonical genes have intrinsic circadian rhythms, especially within the liver and kidney. This new level of complexity applies to the control of renal electrolyte excretion. Furthermore, there is growing evidence that paracrine and autocrine factors, especially the endothelin system, are regulated by clock genes. We have known for decades that excretion of electrolytes is dependent...
Source: Annual Review of Physiology - October 20, 2019 Category: Physiology Authors: Zhang D, Pollock DM Tags: Annu Rev Physiol Source Type: research

Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.
Abstract Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been mo...
Source: Annual Review of Physiology - October 20, 2019 Category: Physiology Authors: Gendron CM, Chakraborty TS, Chung BY, Harvanek ZM, Holme KJ, Johnson JC, Lyu Y, Munneke AS, Pletcher SD Tags: Annu Rev Physiol Source Type: research

Contributions of Aging to Cerebral Small Vessel Disease.
Abstract Cerebral small vessel disease (SVD) is characterized by changes in the pial and parenchymal microcirculations. SVD produces reductions in cerebral blood flow and impaired blood-brain barrier function, which are leading contributors to age-related reductions in brain health. End-organ effects are diverse, resulting in both cognitive and noncognitive deficits. Underlying phenotypes and mechanisms are multifactorial, with no specific treatments at this time. Despite consequences that are already considerable, the impact of SVD is predicted to increase substantially with the growing aging population. In the f...
Source: Annual Review of Physiology - October 15, 2019 Category: Physiology Authors: De Silva TM, Faraci FM Tags: Annu Rev Physiol Source Type: research

Physiology of the Carotid Body: From Molecules to Disease.
ez-Barneo J Abstract The carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation and has a well-recognized role in cardiorespiratory regulation. The CB contains neurosecretory sensory cells (glomus cells), which release transmitters in response to hypoxia, hypercapnia, and acidemia to activate afferent sensory fibers terminating in the respiratory and autonomic brainstem centers. Knowledge of the physiology of the CB has progressed enormously in recent years. Herein we review advances concerning the organization and function of the cellular elements of the CB, with emphasis on the m...
Source: Annual Review of Physiology - October 15, 2019 Category: Physiology Authors: Ortega-Sáenz P, López-Barneo J Tags: Annu Rev Physiol Source Type: research

BMP Signaling in Development, Stem Cells, and Diseases of the Gastrointestinal Tract.
Abstract The bone morphogenetic protein (BMP) pathway is essential for the morphogenesis of multiple organs in the digestive system. Abnormal BMP signaling has also been associated with disease initiation and progression in the gastrointestinal (GI) tract and associated organs. Recent studies using animal models, tissue organoids, and human pluripotent stem cells have significantly expanded our understanding of the roles played by BMPs in the development and homeostasis of GI organs. It is clear that BMP signaling regulates GI function and disease progression that involve stem/progenitor cells and inflammation in ...
Source: Annual Review of Physiology - October 15, 2019 Category: Physiology Authors: Zhang Y, Que J Tags: Annu Rev Physiol Source Type: research

Intestinal Stem Cell Aging: Origins and Interventions.
Abstract Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized i...
Source: Annual Review of Physiology - October 13, 2019 Category: Physiology Authors: Jasper H Tags: Annu Rev Physiol Source Type: research

Circadian Regulation of Cardiac Physiology: Rhythms That Keep the Heart Beating.
Abstract On Earth, all life is exposed to dramatic changes in the environment over the course of the day; consequently, organisms have evolved strategies to both adapt to and anticipate these 24-h oscillations. As a result, time of day is major regulator of mammalian physiology and processes, including transcription, signaling, metabolism, and muscle contraction, all of which oscillate over the course of the day. In particular, the heart is subject to wide fluctuations in energetic demand throughout the day as a result of waking, physical activity, and food intake patterns. Daily rhythms in cardiovascular function...
Source: Annual Review of Physiology - October 6, 2019 Category: Physiology Authors: Zhang J, Chatham J, Young ME Tags: Annu Rev Physiol Source Type: research

Cardiomyocyte Polyploidy and Implications for Heart Regeneration.
Abstract In mammals, most cardiomyocytes (CMs) become polyploid (they have more than two complete sets of chromosomes). The purpose of this review is to evaluate assumptions about CM ploidy that are commonly discussed, even if not experimentally demonstrated, and to highlight key issues that are still to be resolved. Topics discussed here include (a) technical and conceptual difficulties in defining a polyploid CM, (b) the candidate role of reactive oxygen as a proximal trigger for the onset of polyploidy, (c) the relationship between polyploidization and other aspects of CM maturation, (d ) recent insights...
Source: Annual Review of Physiology - October 3, 2019 Category: Physiology Authors: Gan P, Patterson M, Sucov HM Tags: Annu Rev Physiol Source Type: research

Why Lungs Keep Time: Circadian Rhythms and Lung Immunity.
Abstract Circadian rhythms are daily cycles in biological function that are ubiquitous in nature. Understood as a means for organisms to anticipate daily environmental changes, circadian rhythms are also important for orchestrating complex biological processes such as immunity. Nowhere is this more evident than in the respiratory system, where circadian rhythms in inflammatory lung disease have been appreciated since ancient times. In this focused review we examine how emerging research on circadian rhythms is being applied to the study of fundamental lung biology and respiratory disease. We begin with a general i...
Source: Annual Review of Physiology - September 26, 2019 Category: Physiology Authors: Nosal C, Ehlers A, Haspel JA Tags: Annu Rev Physiol Source Type: research

Osteoclasts Provide Coupling Signals to Osteoblast Lineage Cells Through Multiple Mechanisms.
Abstract Bone remodeling is essential for the repair and replacement of damaged and old bone. The major principle underlying this process is that osteoclast-mediated resorption of a quantum of bone is followed by osteoblast precursor recruitment; these cells differentiate to matrix-producing osteoblasts, which form new bone to replace what was resorbed. Evidence from osteopetrotic syndromes indicate that osteoclasts not only resorb bone, but also provide signals to promote bone formation. Osteoclasts act upon osteoblast lineage cells throughout their differentiation by facilitating growth factor release from resor...
Source: Annual Review of Physiology - September 24, 2019 Category: Physiology Authors: Sims NA, Martin TJ Tags: Annu Rev Physiol Source Type: research

Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis.
Abstract Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell-mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting ...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Mazzone M, Bergers G Tags: Annu Rev Physiol Source Type: research

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges.
Abstract Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents-originally developed to starve tumors-could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed ...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Martin JD, Seano G, Jain RK Tags: Annu Rev Physiol Source Type: research