JCI early table of contents for April 24, 2013

There are multiple environmental triggers that contribute to high blood pressure (hypertension), including aging, obesity, stress, alcohol intake, and excess dietary salt; however, the physiological mechanisms that are regulated by these triggers are not fully understood. Blood pressure is controlled in part by the renin angiotensin system (RAS), which manages the release of the hormone angiotensin to control blood vessel constriction. ACE is an enzyme that converts angiotensin to its active form, Ang II, and ACE inhibitors are commonly prescribed to treat hypertension. ACE acts in the kidneys, but also in the systemic circulation, the brain, and many other tissues. In this issue of the Journal of Clinical Investigation, Romer Gonzalez-Villalobos and colleagues at Cedars-Sinai Medical Center in Los Angeles, demonstrated that RAS in the kidneys plays a fundamental role in hypertension. Using transgenic mice, they demonstrated that mice that do not express ACE in the kidney are resistant to hypertension. These findings indicate that ACE plays a fundamental role in the responses of the kidney to conditions that lead to hypertension and suggest that targeting angiotensin production and activation in the kidneys may be an effective approach to treat hypertension. In an accompanying commentary, Timothy Reudelhuber of the University of Montreal discusses how these findings impact our understanding of hypertension.

TITLE: The absence of intrarenal ACE protects against hypertension

AUTHOR CONTACT:
Romer Gonzalez-Villalobos
Cedars-Sinai Medical Center, Los Angeles, CA, USA
Phone: 3104230551; E-mail: romer.gonzalez@csmc.edu

View this article at: http://www.jci.org/articles/view/65460?key=afacf01376ff3cd0acc2

ACCOMPANYING COMMENTARY

TITLE: >Where hypertension happens

AUTHOR CONTACT:
Timothy Reudelhuber
University of Montreal, Montreal, PQ, CAN
Phone: (514) 987-5716; E-mail: Tim.Reudelhuber@ircm.qc.ca

View this article at: http://www.jci.org/articles/view/69296?key=ca4e5c58a7ac9abed6fe

Pancreatic beta cells store and release insulin, the hormone responsible for stimulating cells to convert glucose to energy. The number of beta cells in the pancreas increases in response to greater demand for insulin or injury, but it is not clear if the new beta cells are the result of cell division or the differentiation of a precursor cell, a process known as neogenesis. Knowledge of how beta cells are created and maintained is critical to understanding diseases in which these cells are lost, such as diabetes. In this issue of the Journal of Clinical Investigation, George Gittes and colleagues at the Children's Hospital of Pittsburgh used a fluorescent cell labeling method in mice to determine exactly when precursor cells develop into pancreatic beta cells. They observed neogenesis during embryonic development, but did not find any evidence of neogenesis in adult mice. These data demonstrate that beta cell neogenesis is not possible in adult mice. In a companion commentary, Michael German at the University of California, San Francisco, discusses the experiments that will be required to determine if these findings also apply to humans.

TITLE: No evidence for beta cell neogenesis in murine adult pancreas

AUTHOR CONTACT:
George Gittes
Children's Hospital of Pittsburgh of University of Pittsburgh Medical Cente, Pittsburgh, PA, USA
Phone: 412-692-7291; E-mail: gittesgk@upmc.edu

View this article at: http://www.jci.org/articles/view/66323?key=4eb6fcd0887f4265673b

ACCOMPANYING COMMENTARY

TITLE: Anonymous Sources: Where Do Adult β-Cells Come From?

AUTHOR CONTACT:
Michael German
Univ. of California, San Francisco, San Francisco, CA, USA
Phone: 415/476-9262; Fax: 415-731-3612; E-mail: mgerman@diabetes.ucsf.edu

View this article at: http://www.jci.org/articles/view/69297?key=6b064d7e97fbf4fa75a8

Peripartum cardiomyopathy (PPCM) is a deterioration in cardiac function that occurs in pregnant women during the last month or in the months following their pregnancy. This disorder can occur in women with no prior history of heart disease and the causes are not well understood. In this issue of the Journal of Clinical Investigation, Ingrid Struman and colleagues at the University of Liege in Liege, Belgium, identified a molecule, miR-146a, that can serve as a biomarker for peripartum cardiomyopathy. Struman and colleagues found that expression of miR-146a was induced by the nursing hormone prolactin. MiR-146a expression promoted vascular damage and was increased in a mouse model of PPCM. Conversely, loss of miR-146a in mice prevented PPCM. Importantly, miR-146a expression was elevated in the serum of pregnant women who developed PPCM, suggesting that serum miR-146a levels could predict which patients are at risk for the disease. In a companion commentary, Richard Kitsis of Albert Einstein College of Medicine in New York, discusses the potential implications of this work for the identification and treatment of PPCM.

TITLE: MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy

AUTHOR CONTACT:
Ingrid Struman
University of Liege, Liege, BEL
Phone: +3243663566; E-mail: i.struman@ulg.ac.be

View this article at: http://www.jci.org/articles/view/64365?key=54a58644d5c203c3b462

ACCOMPANYING COMMENTARY

TITLE: A microRNA links prolactin to peripartum cardiomyopathy

AUTHOR CONTACT:
Richard N Kitsis
Albert Einstein College of Medicine, Bronx, NY, USA
Phone: (718) 430-2609; Fax: (718) 430-8989; E-mail: richard.kitsis@einstein.yu.edu

View this article at: http://www.jci.org/articles/view/69286?key=ea00e37108ce3ec09bd1

Muscular dystrophy is a debilitating congenital disorder characterized by progressive muscle weakness and wasting. One of the key obstacles to developing better therapies for this disease is the lack of a non-invasive method to monitor disease progression. In this issue of the Journal of Clinical Investigation, researchers led by Thomas Rando at Stanford University describe a non-invasive method to monitor muscle degeneration in live mice. The technique monitored the expression of a bioluminescent protein in muscle satellite cells, which mediate muscle regeneration and grow in response to muscle damage. In a companion commentary, Kevin Campbell of the University of Iowa discusses how this new technology could potentially be used to evaluate therapeutics that stimulate muscle regeneration.

TITLE: Assessment of disease activity in muscular dystrophies by non-invasive imaging

AUTHOR CONTACT:
Thomas Rando
Stanford University, Stanford, CA, USA
Phone: 650-849-0444; Fax: 650-858-3935; E-mail: rando@stanford.edu

View this article at: http://www.jci.org/articles/view/68458?key=585c77f1bf9a11a15e1c

ACCOMPANYING COMMENTARY

TITLE: Illuminating regeneration: Non-invasive imaging of disease progression in muscular dystrophy

AUTHOR CONTACT:
Kevin Campbell
University of Iowa, Iowa City, IA, USA
Phone: 319-335-8655; Fax: 319-335-6957; E-mail: kevin-campbell@uiowa.edu

View this article at: http://www.jci.org/articles/view/69568?key=752eceb5937a9229fe08

Autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Graves' disease, and systemic lupus erythematosus, are associated with a variant in the gene encoding the protein LYP. In this issue of the Journal of Clinical Investigation, David Rawlings and colleauges at the Seattle Children's Research Institute, generated mice that express an autoimmune disease-associated LYP variant to determine how the protein contributes to autoimmune disorders. They found that expression of the variant alters the function of immune cells. Further, as mice expressing the LYP variant aged, they developed antibodies targeted against their own tissues and exhibited systemic autoimmunity. These findings demonstrate that a naturally-occurring LYP variant impacts the function of the immune system and explains why this gene variant increases susceptibility to autoimmune disorders. In a companion commentary, John Cambier of National Jewish Health and the University of Colorado at Denver discusses how these findings fit with our current understanding of autoimmune diseases.

TITLE: A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

AUTHOR CONTACT:
David Rawlings
Seattle Children's Research Institute, Seattle, WA, USA
Phone: (206) 987-7319; Fax: (206) 987-7310; E-mail: drawling@u.washington.edu

View this article at: http://www.jci.org/articles/view/66963?key=4c855168aaf9c6e8648d

ACCOMPANYING COMMENTARY

TITLE: Genetics of autoimmunity: from mice to men and back again

AUTHOR CONTACT:
John Cambier
National Jewish Health and University of Colorado at Denver, Denver, CO, USA
Phone: 3033981352; Fax: 3032702325; E-mail: cambierj@njhealth.org

View this article at: http://www.jci.org/articles/view/69289?key=bea30596ee494ba2f8c6

Even though cancer cells express proteins that can be detected by immune cells (antigens), they frequently avoid detection and destruction by the immune system (immune evasion). Several new therapeutic strategies are focused on making the immune system better at detecting and killing cancer cells; however, these therapeutics are largely targeted to solid tumors. In this issue of the Journal of Clinical Investigation, Justin Kline and colleagues at the University of Chicago identified a regulatory mechanism that allows acute myeloid leukemia (AML) cells to hide from the immune system. By injecting mice with AML cells, Kline and colleagues found that the cancer cells rapidly hide from the immune system by inducing immune tolerance and subverting the activation of a specific subset of immune cells known as T cells. Treating the mice with an antibody targeting the protein CD40 protected the T cells and allowed them to become active, leading to the elimination of the cancerous cells and prolonging the survival of AML cell-bearing mice. These findings indicate that AML cells induce T cell-mediated tolerance to evade the immune system. Further, these results provide a rationale for evaluating CD40 antibodies for the treatment of AML.

TITLE: CD40 ligation reverses T cell tolerance in acute myeloid leukemia

AUTHOR CONTACT:
Justin Kline
The University of Chicago, Chicago, IL, USA
Phone: (773) 702-5550; E-mail: jkline@medicine.bsd.uchicago.edu

View this article at: http://www.jci.org/articles/view/63980?key=99fe4f964c61b7104d5a

The complement system is an immune response that helps antibodies and immune cells clear pathogens from the body. It consists of a number of small proteins in the blood that circulate as inactive precursor proteins. During complement activation, a protein known as C3 is cleaved into smaller fragments that bind to tissue surfaces, initiating a cascade that targets specific cells for destruction. C3 accumulation on tissues is a marker for tissue inflammation. In this issue of the Journal of Clinical Investigation, Joshua Thurman and colleagues at the University of Colorado at Denver report the development of antibodies that specifically recognize tissue-bound C3 fragments. The authors hope that this new technology can be used to develop diagnostic and therapeutic tools for diseases associated with tissue inflammation.

TITLE: Detection of complement activation using monoclonal antibodies to C3d

AUTHOR CONTACT:
Joshua Thurman
University of Colorado Denver, Aurora, CO, USA
Phone: 303-724-7584; Fax: 303-724-7581; E-mail: joshua.thurman@ucdenver.edu

View this article at: http://www.jci.org/articles/view/65861?key=f5fd75674e3ed56878bb