July 2005
JCI table of contents July 1, 2005
EDITOR'S PICK
Eliminating bacterial infections out of thin air
When microorganisms invade the body, immune mechanisms kick in to fight them off. The infected tissues typically show depleted oxygen levels, and a protein called HIF-1 alpha regulates this. Interestingly, the cells responsible for destroying the foreign pathogens are effective in this low-oxygen environment. In a new study appearing in the July 1 print issue of The Journal of Clinical Investigation, Randall Johnson and collegues from UCSD show for the first time that induction of the HIF-1 pathway can act as a "super-antibiotic", accelerating the killing of bacteria in conditions typical of those found during bacterial infection and sepsis.
The authors show that regulation of HIF-1 is required for immune defense against bacterial infection. They also show that bacteria killing is increased under conditions of low oxygen due to HIF-1 upregulation, and that bacterial infection upregulates HIF-1. In fact, upregulation of HIF-1 enhances expression of bactericidal agents and killing of bacteria.
This reveals that a novel approach to treating bacterial infection is by increasing the killing capacity of cells of the innate immune system. In a related commentary, Kol Zarember and Harry Melach write, "By dissecting the role of HIF-1 in innate immune defenses, the study�introduces new targets for therapeutic immunomodulation."
TITLE: HIF-1alpha expression regulates the bactericidal capacity of phagocytes
AUTHOR CONTACT:
Randall Johnson
University of California, San Diego, La Jolla, CA USA
Phone: 858 822-0509; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=23865
ACCOMPANYING COMMENTARY:
Title: HIF-1alpha: a master regulator of innate host defenses?
AUTHOR CONTACT:
Harry L. Malech
NIAID, National Institutes Of Health, Bethesda, MD USA
Phone: 301-480-6916; Fax: 301-402-0789; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25740
PHYSIOLOGY
Muscles in obesity have problems choosing fuel
In obese and diabetic people, fat and carbohydrate oxidation by skeletal muscle is disrupted, contributing to insulin resistance. In a new study appearing in the July 1 print issue of The Journal of Clinical Investigation, Barbara Ukropcova and colleagues from Pennington Biomedical Research Center examine whether the ability of skeletal muscle to oxidize fat in vitro is representative of the donor's metabolic characteristics.
The authors find that skeletal muscle cells, cultured in a controlled environment for up to 5 weeks, isolated from the endocrine and nutritional influences of their donor, retained their donor's metabolic characteristics. This suggests that defects in switching between fat oxidation and carbohydrate oxidation, possibly due to genetic defects in skeletal muscle, contribute to obesity and insulin resistance. The authors show that fuel preference in muscle cells is abnormal in young healthy obese individuals.
In an accompanying commentary, David Kelley writes, "these findings support the concept that the capacity of skeletal muscle to oxidize fat under appropriate physiological conditions is related to leanness, aerobic fitness, and insulin sensitivity."
TITLE: Dynamic Changes in Fat Oxidation in Human Primary Myocytes Mirror Metabolic Characteristics of the Donor
AUTHOR CONTACT:
Barbara Ukropcova
Pennigton Biomedical Research Center, Baton Rouge, LA USA
Phone: 225-763-2726; Fax: 225-763-2525; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24332
ACCOMPANYING COMMENTARY:
TITLE: Skeletal muscle fat oxidation: timing and flexibility are everything
AUTHOR CONTACT:
David Kelley
University of Pittsburgh School of Medicine, Pittsburgh, PA USA
Phone: 412-692-2848; Fax: 412-692-2165; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25758
PHYSIOLOGY
A new stem cell niche � no kidneying around
A common disease of the kidney is acute renal failure (ARF) that causes kidney damage and abnormal function. The kidney is capable of some regeneration and it was previously thought that stem cells from the bone marrow were at least partially responsible for this repair. Two new JCI studies now challenge this hypothesis.
In a new study appearing in the July 1 print issue of The Journal of Clinical Investigation, Jeremy Duffield and colleagues from Harvard study kidney repair in mice harboring markers in their bone marrow. The researchers show that bone marrow-derived cells do not contribute to kidney repair after ARF. The marked cells were not incorporated into the injured kidney. The authors hypothesize that endogenous kidney cells instead are responsible for the repair seen. The second study, by Fangming Lin and colleagues from University of Texas, also shows that cells within the kidney are the main source of kidney repair. Moreover, injection of bone marrow cells does not make any significant contribution to functional or structural recovery.
In an accompanying commentary, Diane Kraus and Lloyd Cantley write, "the majority of the cells that�repair the injured tubules came from an endogenous cell population, rather than from bone marrow-derived cells." These results support the premise that the kidney has a stem cell niche of its own.
TITLE: Restoration of tubular epithelial cells during repair of the post ischemic kidney is independent of bone marrow stem cells
AUTHOR CONTACT:
Jeremy Duffield
Harvard Institutes of Medicine, Boston, MA USA
Phone: 617-525-5914; Fax: 617-525-5830; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=22593
TITLE: Intrarenal Cells, not Bone Marrow-Derived Cells, are the Major Source for Regeneration in Post-ischemic Kidney
AUTHOR CONTACT:
Fangming Lin
University of Texas Southwestern Medical Center, Dallas, TX USA
Phone: 214-648-3438; Fax: 214-648-2034; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=23015
ACCOMPANYING COMMENTARY:
TITLE: Heating up the stem cell controversy: protection rather than differentiation in the kidney tubule?
AUTHOR CONTACT:
Lloyd G. Cantley
Yale University School of Medicine, New Haven, CT USA
Phone: 203-785-7110; Fax: 203-785-4904; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25540
PHYSIOLOGY
A new way to keep blood pressure under control
Chromogranin A (CHGA) is a hormone-like molecule that is overexpressed in hereditary hypertension, but its precise role in the disease was unclear. In a new study appearing in the July 1 print issue of The Journal of Clinical Investigation, Sushil Mahata and colleagues from UCSD describe several novel phenotypes observed in mice lacking CHGA, and establish a role for this protein in hormone and neurotransmitter storage and release in vivo.
The mice had elevated blood pressure that could be restored to normalcy by treating the mice with human CHGA, demonstrating that the human gene plays a role in autonomic control of blood pressure. An accompanying commentary by Taeyoon Kim and Y. Peng Loh states that one important clinical implication of this work is that CHGA may be used as a therapeutic agent for treating hypertension in humans.
TITLE: Targeted ablation of the chromogranin A gene: Elevated blood pressure rescued by the human ortholog
AUTHOR CONTACT:
Sushil Mahata
University of California, San Diego, La Jolla, CA USA
Phone: 858-552-8585 x2637; Fax: 858-642-6425; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24354
ACCOMPANYING COMMENTARY:
TITLE: Chromagranin A: a surprising link between granule biogenesis and hypertension
AUTHOR CONTACT:
Y. Peng Loh
NICHD, NIH, Bethesda, MD USA
Phone: 301-496-3239; Fax: 301-496-9939; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25706
PHYSIOLOGY
Unraveling the regulation of renin
Renin is a protein that controls blood pressure and is increased in many cardiovascular diseases and kidney diseases. Liver X Receptors (LXR) are members of the nuclear hormone receptor family that play a role in lipid metabolism, inflammation and immunity. In a new study appearing in the July 1 print issue of The Journal of Clinical Investigation, Victor Dzau and colleagues from Duke University establish the role of LXR alpha and LXR beta as regulators of renin. The data provide information for the development of novel selective modulators of LXR alpha and beta for several disorders including hypertension and heart failure.
TITLE: Liver X Receptors alpha and beta regulate renin expression in vivo
AUTHOR CONTACT:
Victor Dzau
Duke University, Durham, NC USA
Phone: 919-684-2255; Fax: 919-681-7020; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24594
GENETICS
Cause of deadly skin disease found to be in the genes
Harlequin ichthyosis (HI) is a severe skin disease that is usually lethal in newborns. A dense scale that covers the skin, with abnormal facial features, characterizes it. The cause of HI was previously unknown. In a new study appearing in the July 1 print issue of The Journal of Clinical Investigation, Masashi Akiyama and colleagues from Hokkaido University report that mutations in a protein called ABCA12 are responsible for HI.
In this study, the authors show that ABCA12 is a lipid transporter in skin cells. They identify 5 mutations in 4 HI families.
In an accompanying commentary, Alain Hovnanian writes, "these results should allow for early prenatal diagnosis of HI and lend hope to the possibility of a specific treatment for this devastating disorder."
TITLE: Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer
AUTHOR CONTACT:
Masashi Akiyama
Hokkaido University Graduate School of Medicine, Sapporo, Japan Phone: 81-117161161; Fax: 81-117067820; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24834
ACCOMPANYING COMMENTARY:
TITLE: Harlequin ichthyosis unmasked: a defect of lipid transport
AUTHOR CONTACT:
Alain Hovnanian
Purpan Hospital, INSERM Toulouse, France
Phone: 33-561-158-432; Fax: 33-561-499-036; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25736