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- Volume 75, 2013
Annual Review of Physiology - Volume 75, 2013
Volume 75, 2013
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Claudins and the Kidney
Vol. 75 (2013), pp. 479–501More LessClaudins are tight junction membrane proteins that regulate paracellular permeability of renal epithelia to small ions, solutes, and water. Claudins interact within the cell membrane and between neighboring cells to form tight junction strands and constitute both the paracellular barrier and the pore. The first extracellular domain of claudins is thought to be the pore-lining domain and contains the determinants of charge selectivity. Multiple claudins are expressed in different nephron segments; such differential expression likely determines the permeability properties of each segment. Recent evidence has identified claudin-2 as constituting the cation-reabsorptive pathway in the proximal tubule; claudin-14, -16, and -19 as forming a complex that regulates calcium transport in the thick ascending limb of the loop of Henle; and claudin-4, -7, and -8 as determinants of collecting duct chloride permeability. Mutations in claudin-16 and -19 cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. The roles of other claudins in kidney diseases remain to be fully elucidated.
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Fibroblast Growth Factor 23 and Klotho: Physiology and Pathophysiology of an Endocrine Network of Mineral Metabolism
Vol. 75 (2013), pp. 503–533More LessThe metabolically active and perpetually remodeling calcium phosphate–based endoskeleton in terrestrial vertebrates sets the demands on whole-organism calcium and phosphate homeostasis that involves multiple organs in terms of mineral flux and endocrine cross talk. The fibroblast growth factor (FGF)-Klotho endocrine networks epitomize the complexity of systems biology, and specifically, the FGF23-αKlotho axis highlights the concept of the skeleton holding the master switch of homeostasis rather than a passive target organ as hitherto conceived. Other than serving as a coreceptor for FGF23, αKlotho circulates as an endocrine substance with a multitude of effects. This review covers recent data on the physiological regulation and function of the complex FGF23-αKlotho network. Chronic kidney disease is a common pathophysiological state in which FGF23-αKlotho, a multiorgan endocrine network, is deranged in a self-amplifying vortex resulting in organ dysfunction of the utmost severity that contributes to its morbidity and mortality.
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Phosphate Transporters and Their Function
Vol. 75 (2013), pp. 535–550More LessPlasma phosphate concentration is maintained within a relatively narrow range by control of renal reabsorption of filtered inorganic phosphate (Pi). Pi reabsorption is a transcellular process that occurs along the proximal tubule. Pi flux at the apical (luminal) brush border membrane represents the rate-limiting step and is mediated by three Na+-dependent Pi cotransporters (members of the SLC34 and SLC20 families). The putative proteins responsible for basolateral Pi flux have not been identified. The transport mechanism of the two kidney-specific SLC34 proteins (NaPi-IIa and NaPi-IIc) and of the ubiquitously expressed SLC20 protein (PiT-2) has been studied by heterologous expression to reveal important differences in kinetics, stoichiometry, and substrate specificity. Studies on the regulation of the abundance of the respective proteins highlight significant differences in the temporal responses to various hormonal and nonhormonal factors that can influence Pi homeostasis. The phenotypes of mice deficient in NaPi-IIa and NaPi-IIc indicate that NaPi-IIa is responsible for most Pi renal reabsorption. In contrast, in the human kidney, NaPi-IIc appears to have a relatively greater role. The physiological relevance of PiT-2 to Pi reabsorption remains to be elucidated.
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Claudin Heterogeneity and Control of Lung Tight Junctions
Vol. 75 (2013), pp. 551–567More LessLung epithelial cells interconnected by tight junctions provide a barrier to the free diffusion of solutes into airspaces. Transmembrane tight junction proteins known as claudins are essential for epithelial barrier function. Claudins are regulated through interactions with each other that are coordinated with other transmembrane tight junction proteins and cytosolic scaffold proteins. Of the 14 claudins expressed by the alveolar epithelium, claudin-3, claudin-4, and claudin-18 are the most prominent; each confers unique properties to alveolar barrier function. In particular, a protective role for claudin-4 in preventing lung injury has emerged. By contrast, lung diseases that affect claudin expression and impair barrier function, including alcoholic lung syndrome and sepsis, prime the lung for pulmonary edema. Thus, approaches to restore and/or augment lung claudin expression provide potential targets for promoting healthy barrier function.
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Platelets in Lung Biology
Vol. 75 (2013), pp. 569–591More LessPlatelets and the lungs have an intimate relationship. Platelets are anucleate mammalian blood cells that continuously circulate through pulmonary vessels and that have major effector activities in hemostasis and inflammation. The lungs are reservoirs for megakaryocytes, the requisite precursor cell in thrombopoiesis, which is the intricate process by which platelets are generated. Platelets contribute to basal barrier integrity of the alveolar capillaries, which selectively restricts the transfer of water, proteins, and red blood cells out of the vessels. Platelets also contribute to pulmonary vascular repair. Although platelets bolster hemostatic and inflammatory defense of the healthy lung, experimental evidence and clinical evidence indicate that these blood cells are effectors of injury in a variety of pulmonary disorders and syndromes. Newly discovered biological capacities of platelets are being explored in the context of lung defense, disease, and remodeling.
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Regulation and Repair of the Alveolar-Capillary Barrier in Acute Lung Injury
Vol. 75 (2013), pp. 593–615More LessConsiderable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair.
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The Ins and Outs of Aging and Longevity*
Vol. 75 (2013), pp. 617–619More LessAs a nod to the oft-quoted evolutionary theorist George Williams, “It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed” (1). How and why we age are mysteries of the ages (2, 3). The “how” of this mystery is the purview of experimental biologists who try to understand the basic processes that lead to system maintenance failure—from the level of molecules to that of entire organisms—that we term “aging”. The “why” of this mystery is the purview of evolutionary theorists whose ideas shape the questions that biogerontologists pose, on the basis of the premise put forth by another preeminent geneticist and evolutionary biologist, Theodosius Dobzhansky, that “[n]othing in biology makes sense except in the light of evolution” (4). These experimental and evolutionary perspectives converge in the modern science of aging, and its curious cousin “longevity”, in an attempt to unify extensive findings from diverse areas of biology (5).
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Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts
Vol. 75 (2013), pp. 621–644More LessDiscovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging. This network includes the insulin/IGF-1 and target of rapamycin (TOR) pathways and likely mediates the effects of dietary restriction on aging. Yet the biological processes upon which these pathways act to control life span remain unclear. A long-standing guiding assumption about aging is that it is caused by wear and tear, particularly damage at the molecular level. One view is that reactive oxygen species (ROS), including free radicals, generated as by-products of cellular metabolism, are a major contributor to this damage. Yet many recent tests of the oxidative damage theory have come up negative. Such tests have opened an exciting new phase in biogerontology in which fundamental assumptions about aging are being reexamined and revolutionary concepts are emerging. Among these concepts is the hyperfunction theory, which postulates that processes contributing to growth and reproduction run on in later life, leading to hypertrophic and hyperplastic pathologies. Here we reexamine central concepts about the nature of aging.
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Genome Instability and Aging
Jan Vijg, and Yousin SuhVol. 75 (2013), pp. 645–668More LessGenome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens. To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence. Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations. There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging. The exception is cancer, an age-related disease caused by the accumulation of mutations and epimutations. Here, we first review current concepts regarding the relationship between DNA damage, repair, and mutation, as well as the data regarding genome alterations as a function of age. We then describe a model for how randomly induced DNA sequence and epigenomic variants in the somatic genomes of animals can result in functional decline and disease in old age. Finally, we discuss the genetics of genome instability in relation to longevity to address the importance of alterations in the somatic genome as a causal factor in aging and to underscore the opportunities provided by genetic approaches to develop interventions that attenuate genome instability, reduce disease risk, and increase life span.
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Metabolic and Neuropsychiatric Effects of Calorie Restriction and Sirtuins
Vol. 75 (2013), pp. 669–684More LessMost living organisms, including humans, age. Over time the ability to do physical and intellectual work deteriorates, and susceptibility to infectious, metabolic, and neurodegenerative diseases increases, which leads to general fitness decline and ultimately to death. Work in model organisms has demonstrated that genetic and environmental manipulations can prevent numerous age-associated diseases, improve health at advanced age, and increase life span. Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust manipulation, genetic or environmental, to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less certain. Understanding the molecular mechanisms of CR may lead to the development of novel therapies to combat diseases of aging and to improve the quality of life. Sirtuins, a family of NAD+-dependent enzymes, mediate a number of metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions. We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior.
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Aging, Cellular Senescence, and Cancer
Vol. 75 (2013), pp. 685–705More LessFor most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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Previous Volumes
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Volume 87 (2025)
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Volume 86 (2024)
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Volume 85 (2023)
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Volume 84 (2022)
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Volume 83 (2021)
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Volume 82 (2020)
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Volume 81 (2019)
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Volume 80 (2018)
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Volume 79 (2017)
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Volume 78 (2016)
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Volume 77 (2015)
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Volume 76 (2014)
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Volume 75 (2013)
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Volume 74 (2012)
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Volume 73 (2011)
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Volume 72 (2010)
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Volume 71 (2009)
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Volume 70 (2008)
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Volume 69 (2007)
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Volume 68 (2006)
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Volume 67 (2005)
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Volume 66 (2004)
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Volume 65 (2003)
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Volume 64 (2002)
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Volume 63 (2001)
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Volume 62 (2000)
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Volume 61 (1999)
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Volume 60 (1998)
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Volume 59 (1997)
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Volume 58 (1996)
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Volume 57 (1995)
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Volume 56 (1994)
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Volume 55 (1993)
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Volume 54 (1992)
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Volume 53 (1991)
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Volume 52 (1990)
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Volume 51 (1989)
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Volume 50 (1988)
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Volume 49 (1987)
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Volume 48 (1986)
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Volume 47 (1985)
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Volume 46 (1984)
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Volume 45 (1983)
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Volume 44 (1982)
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Volume 43 (1981)
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Volume 42 (1980)
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Volume 41 (1979)
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Volume 40 (1978)
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Volume 39 (1977)
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Volume 38 (1976)
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Volume 37 (1975)
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Volume 36 (1974)
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Volume 35 (1973)
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Volume 34 (1972)
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Volume 33 (1971)
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Volume 32 (1970)
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Volume 31 (1969)
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Volume 30 (1968)
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Volume 29 (1967)
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Volume 28 (1966)
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Volume 27 (1965)
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Volume 26 (1964)
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Volume 25 (1963)
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Volume 24 (1962)
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Volume 23 (1961)
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Volume 22 (1960)
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Volume 21 (1959)
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Volume 20 (1958)
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Volume 19 (1957)
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Volume 18 (1956)
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Volume 17 (1955)
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Volume 16 (1954)
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Volume 15 (1953)
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Volume 14 (1952)
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Volume 13 (1951)
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Volume 12 (1950)
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Volume 11 (1949)
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Volume 10 (1948)
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Volume 9 (1947)
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Volume 8 (1946)
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Volume 7 (1945)
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Volume 6 (1944)
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Volume 5 (1943)
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Volume 4 (1942)
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Volume 3 (1941)
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Volume 2 (1940)
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Volume 1 (1939)
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Volume 0 (1932)