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Thirty Years of Intracrinology

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Thirty Years of Intracrinology The Ochsner Journal 14:673–680, 2014 Ó Academic Division of Ochsner Clinic Foundation Thirty Years of Intracrinology Richard N. Re, MD Research Division, Ochsner Health System, New Orleans, LA lular signaling molecules and could also act in the ABSTRACT intracellular space: these varied factors displayed Background: Intracrinology is the study of the intracellular intracrine functionality. Surprisingly, included among actions, regulation, trafficking, and interactions of extracellular these proteins were growth factors, cytokines, tran- signaling peptides/proteins. scription factors, DNA binding proteins, and en- 1-9 Methods: We describe the development of intracrine biology zymes. since the term was defined in 1984. We developed the basic principles of intracrine action based on observing the functionality of various Results: Intracrine biology plays a role in many normal and intracrines.10-43 For example, many intracrines upre- pathological processes and represents a fertile field for the gulate either their own synthesis or the synthesis of development of novel therapeutics. elements of their signaling cascades. Intracrines can Conclusion: Although 30 years old, the field of intracrinology is operate in positive feedback loops—that is, in what only now becoming widely accepted. Intracrine principles can has been termed a feed-forward mode. For example, be applied to the investigation of physiological processes and angiotensin II action at the nucleus can upregulate the to the development of new therapies. transcription of renin and angiotensinogen. Investiga- tors have reported that high glucose levels stimulate the synthesis of intracellular angiotensin II and establish a feed-forward loop in which angiotensin II INTRODUCTION upregulates angiotensinogen.35,38 This feed-forward In 1984, this laboratory introduced the term loop appears to play a role in diabetes-related intracrine, meaning the action of a peptide hormone pathology and in particular diabetic cardiomyopathy. within a cell as opposed to acting at cell surface Also, in some cases, intracrines can travel to target receptors. Intracrine action could involve the action of cells, be internalized, and act in those cells, including a hormone or other extracellular signaling peptide/ setting up feed-forward loops. This action results in a protein in its cell of synthesis or in target cells after change of state of the target cells. Indeed, if the internalization. This notion grew out of studies by our secretion of an intracrine ceases, the target cells group and others of the intracellular trafficking and remain in an altered state by virtue of the intracellular actions of the vasoactive peptide angiotensin II. In feed-forward loop. This has the result of producing a time, it became clear that peptides/proteins, not novel form of differentiation, one based on active usually thought of as hormones, served as extracel- feed-forward loops. If target cells in turn secrete intracrines to affect nearby cells, a wave of differen- tiation can propagate through a tissue. Again, Address correspondence to intracellular feed-forward loops can maintain the Richard N. Re, MD differentiated state, even after secretion ceases. As Scientific Director an example, one can look to the homeodomain Research Division transcription factors that are intracrines. Each of these Ochsner Health System factors contains a cell penetration sequence that 1514 Jefferson Hwy. enables it to enter target cells. One such factor, when New Orleans, LA 70121 applied to pancreatic duct cells, enters the cells, Tel: (504) 842-3700 upregulates its own synthesis, and converts the Email: [email protected] ductal cells into islet cells. It appears that intracrines Keywords: Angiotensin II, cytoplasmic and nuclear receptors, can traffick between cells in a variety of ways intracellular signaling peptides and proteins, intracrine, including in the fluid phase following secretion, intracrinology, renin-angiotensin systems traveling in lipid bodies called exosomes that are frequently released by cells in a variety of circum- The author has no financial or proprietary interest in the subject stances, or potentially between cells in thin nano- matter of this article. tubes. Many intracrines traffick to the nucleolus; these Volume 14, Number 4, Winter 2014 673 Thirty Years of Intracrinology intracrines almost invariably are either angiogenic or could generate physiologically active angiotensin II in antiangiogenic.13,14,16,17,22,24 the intracellular space.12,19,54 Indeed, high glucose Although not all intracrines display all the charac- was later shown to upregulate an intracellular renin- teristics of intracrine function, these notions form the angiotensin system in cardiac myocytes and cardiac basis of a coherent view of intracrine functionality, a fibroblasts, leading to increased intracellular angio- view that surprisingly has been demonstrated to have a tensin II levels. This finding fit nicely with the heuristic and predictive value. These ideas serve as the previously demonstrated increased angiotensin II in basis of a coherent branch of study, intracrinology. cardiac myocytes from patients suffering from diabet- Here we discuss some of the findings and implications ic cardiomyopathy.17,18,28,54 Finally, a transgenic of this approach. This discussion cannot be compre- mouse line was developed that overexpressed an- hensive and, given space constraints, must be giotensin II intracellularly but not extracellularly.34,40 somewhat superficial in its treatment of the topic. These animals became hypertensive and developed Although only a few representative examples of the renal thrombotic microangiopathy. In this model, application of intracrinology can be discussed, much nuclear localization of internally synthesized angio- of this subject matter has been reviewed in more depth tensin II was found, but the binding of the hormone to in prior publications. While the intracrine hypothesis mitochondria was much more prevalent. Indeed, the originated at Ochsner Clinic Foundation, many scien- binding of angiotensin II to 2 specific mitochondrial tists around the world have provided the data that electron chain proteins was demonstrated, and the support it. It is not possible to credit or reference all binding was associated with altered generations of these talented people in a short article. References in reactive oxygen species, long assumed to play a role this manuscript primarily arise from this institution, but in angiotensin II-induced pathology. This observation these references cite the work of the many others who pointed out that future studies of intracrine biology in have made progress possible in this field (Table).1-54 general, and angiotensin II biology in particular, must take into account what we called noncanonical intra- INTRACRINOLGY AND THE crine action––that is, an intracrine’s action indepen- CARDIOVASCULAR SYSTEM dent of its canonical action at its typical receptors.38 The first evidence of intracellular peptide action This in turn implied that total blockade of angiotensin was discovered when tritiated angiotensin II was II action could not be achieved with receptor blockers injected into rats that were immediately killed and alone. Any therapeutic implications of this observation subjected to electron microscope autoradiography. remain to be determined. Another line of investigation Angiotensin II-associated radioactivity was found in involved the direct physical introduction of angioten- the nucleus and mitochondria of the rat cells. Then sin II into cardiac myocytes. Clear effects on cellular specific angiotensin II receptors were described on electrical conductance were observed, and these cell nuclei and also in association with euchromatin. potentially have an important role to play in arrhyth- The binding of angiotensin II to the nuclei upregulated mogenesis.12,15,16,18-43 gene transcription and produced changes in nucleo- Although the study of intracrine angiotensin II led some/chromatin structure consistent with enhanced the way toward the study of intracrine processes, transcriptional activity. A variety of laboratories report- especially in the cardiovascular system, other intra- ed angiotensin II AT-1 and AT-2 receptors on isolated crines also pointed the way. Parathyroid hormone- nuclei, but it was only years later that electromicro- related protein (PTHrP), a hormone associated with scopic immunohistology confirmed angiotensin II in the hypercalcemia of malignancy, is an intracrine. association with euchromatin.1-8,10,11 Collectively, One form of the protein is retained in the intracellular these findings indicate that angiotensin II binds to space and acts at the nucleus. Another form of the several nuclear sites and regulates transcription. protein is secreted to act at cell-surface receptors. In Studies of fluorescently labeled AT-1 receptors vascular smooth muscle cells, the binding of the demonstrated that angiotensin II binding to cell hormone to the nucleus is associated with increased surface receptors could lead to their internalization cellular proliferation, while the binding to the cell and nuclear translocation. Moreover, a variety of surface receptor is antiproliferative. This example models was employed to demonstrate that angioten- points out some of the complexity of intracrine sin II binding to nuclei in vivo could be associated with biology. Other studies showed the important role of cellular proliferation or hypertrophy.11-18,23,28,54 The intracrine loops in embryonic
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