News From The Journal Of Clinical Investigation, April 20, 2009

Main Category: Biology / Biochemistry
Also Included In: Infectious Diseases / Bacteria / Viruses;  Cardiovascular / Cardiology;  Cystic Fibrosis
Article Date: 22 Apr 2009 - 2:00 PDT

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VIROLOGY: New gene regions linked with susceptibility to HIV-1-associated kidney disease

HIV-1-associated nephropathy (HIVAN) is a kidney disease that occurs commonly in individuals infected with HIV-1. Several studies have linked variants of genes expressed in kidney cells known as podocytes to HIVAN. Using a genetic analysis approach known as expression quantitative trait locus analysis, Ali Gharavi and colleagues, at Columbia University College of Physicians and Surgeons, New York, have now identified new genetic regions associated with kidney disease in a mouse model of HIVAN. As noted by Susan E. Quaggin, at the University of Toronto, Toronto, analysis of corresponding regions of the human genome may well shed new light on genetic susceptibility to HIVAN in humans.

In the study, the initial genetic analysis revealed two new genetic regions associated with kidney disease in the mouse model of HIVAN, HIVAN2 and HIVAN3. Analysis of genes expressed by podocytes indicated that HIVAN2 and HIVAN1 (a genetic region previously associated with HIVAN in mice) markedly affected the levels of expression of Nphs2. Surprisingly, HIVAN1 and HIVAN2 did not contain Nphs2, but regulated the expression of networks of genes expressed by podocytes, thereby impacting expression of Nphs2. As the gene networks modified by these two genetic regions were not completely identical, the authors suggest that the affected genes in HIVAN1 and HIVAN2 impact different points within the network.

TITLE: Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

AUTHOR CONTACT:
Ali G. Gharavi
Columbia University College of Physicians and Surgeons, New York, New York, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37131

ACCOMPANYING COMMENTARY

TITLE: Genetic susceptibility to HIV-associated nephropathy

AUTHOR CONTACT:
Susan E. Quaggin
The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

View the PDF of this article at: https://www.the-jci.org/article.php?id=39254

CARDIOLOGY: From enlarged heart to heart failure: a key role for the protein CaMKII-delta

One of the leading causes of death in the developed world is heart failure, which is usually preceded by cardiac hypertrophy (an increase in the size of the heart muscle cells). Previous studies have suggested the protein CaMKII has a role in cardiac hypertrophy and heart failure. Now, Joan Heller Brown and colleagues, at the University of California at San Diego, La Jolla, have generated mice lacking a specific form of CaMKII (CaMKII-delta) and used them to show that the major role of CaMKII-delta in the heart is in the progression of cardiac hypertrophy to heart failure

In the study, mice lacking CaMKII-delta and normal mice showed the same increase in heart weight and heart muscle cell size after they had been experimentally manipulated to have high blood pressure in the blood vessel leading to the heart (high blood pressure can be a cause of cardiac hypertrophy). This cardiac hypertrophy persisted in the CaMKII-delta-deficient mice but did not progress to heart failure, as it did in the normal mice. Further analysis provided insight into the mechanisms underlying the role of CaMKII-delta in the progression of cardiac hypertrophy to heart failure. The authors and, in an accompanying commentary, Mark Anderson, at University of Iowa Carver College of Medicine, Iowa City, therefore suggest that targeting CaMKII might provide a way to prevent the development of heart failure in individuals with cardiac hypertrophy.

TITLE: Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice

AUTHOR CONTACT:
Joan Heller Brown
University of California at San Diego, La Jolla, California, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38022

ACCOMPANYING COMMENTARY

TITLE: CaMKII and a failing strategy for growth in heart

AUTHOR CONTACT:
Mark E. Anderson
University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=39262

NEPHROLOGY: Immune cells hurt the kidney

One correlate of the progression of kidney diseases such as glomerulonephritis to kidney failure is the accumulation of immune cells in a region of the kidney known as the tubulointerstitium. Although the identity of these immune cells is known (they include Th cells, CTLs, and DCs), their precise role in disease progression has not been determined. However, Christian Kurts and colleagues, at Friedrich-Wilhelms-Universität, Germany, have now developed a new transgenic mouse model of glomerulonephritis and found that these immune cells cooperate to contribute to disease progression. A particularly important role for DCs was indicated by the fact that when the transgenic mice were depleted of DCs the kidney damage caused jointly by Th cells and CTLs resolved.

In an accompanying commentary, Andrey Shaw and colleagues, at Washington University School of Medicine, St. Louis, highlight the fact that these data clearly indicate T cells (both Th cells and CTLs) have a causative role in glomerulonephritis and discuss some of the future opportunities that this new model provides for furthering our understanding of the progression of glomerulonephritis to kidney failure.

TITLE: Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury

AUTHOR CONTACT:
Christian Kurts
Friedrich-Wilhelms-Universität, Bonn, Germany.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38399

ACCOMPANYING COMMENTARY

TITLE: New roles revealed for T cells and DCs in glomerulonephritis

AUTHOR CONTACT:
Andrey S. Shaw
Washington University School of Medicine, St. Louis, Missouri, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=39071

NEUROBIOLOGY: New insights into brain tissue injury following ischemic stroke

The accumulation of cells, particularly blood cells known as platelets and inflammatory cells, at sites of oxygen depletion (ischemia) in the brain can exacerbate the brain damage following ischemic stroke. The protein CD39 on the surface of cells that line blood vessels (endothelial cells) reduces platelet accumulation in the ischemic brain; however, the role of this protein on inflammatory cells and their accumulation in this context has not been determined. In a new study, Matthew Hyman and colleagues, at the University of Michigan Medical Center, Ann Arbor, have revealed that CD39 reduces the accumulation of inflammatory cells and the reactivity of platelets in the ischemic brain, thereby mitigating brain tissue injury following ischemic stroke. Using CD39-deficient mice, the researchers demonstrated that CD39 is vital for the molecular reactions that underlie the regulation of platelet reactivity and the suppression of inflammatory cell trafficking to injury sites. These and other data in the study highlight a link between CD39 on both endothelial cells and inflammatory cells and inflammatory cell trafficking and platelet reactivity that reduces brain tissue injury following ischemic stroke.

TITLE: Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39

AUTHOR CONTACT:
Matthew C. Hyman
University of Michigan Medical Center, Ann Arbor, Michigan, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36433

PULMONARY: Molecular insight into increased risk of lung infections in those with cystic fibrosis

Chronic bacterial infections of the airways are one of the major causes of death in individuals with cystic fibrosis, an inherited disease caused by disruption to the function of the CFTR protein. Jeffrey Wine and colleagues, at Stanford University, California, have now provided new molecular insight into how disruption of CFTR function in the human lung impairs the secretion of fluids that are required for the action of immune defense mediators in the lung.

The fluids important for immune mediators in the lungs are released from airway glands known as submucosal glands following stimulation by nerves that release a number of factors, including substance P. In the study, fluid secretion mediated by substance P was measured from isolated human submucosal glands and intact lung transplant tissue. Irritants were unable to stimulate substance P-induced production of fluids by glands from individuals with cystic fibrosis. Further, glands from individuals with cystic fibrosis did not respond to substance P, whereas glands from healthy individuals secreted fluids. The authors therefore conclude that CFTR is required for substance P-induced production of fluids by submucosal glands and suggest that a defect in this pathway following exposure to lung irritants contributes to the susceptibility to airway infection seen in individuals with cystic fibrosis.

TITLE: Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process

AUTHOR CONTACT:
Jeffrey J. Wine
Stanford University, Stanford, California, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37284

PULMONARY: A complex web of lung scarring, cell death, and high blood pressure in blood vessels of the lung

Although lung tissue scarring (pulmonary fibrosis) is frequently associated with high blood pressure in the blood vessels that supply the lung (a condition known as pulmonary hypertension), the mechanisms underlying the development of pulmonary hypertension in this setting remain unknown. However, a new study, by Martin Kolb and colleagues, at McMaster University, Hamilton, has revealed a link between the development of pulmonary hypertension in rats with pulmonary fibrosis and a form of cell death known as apoptosis.

In the study, rats treated with the protein TGF-β1, which induced pulmonary fibrosis, exhibited increased apoptosis of the cells that line blood vessels in the lung (endothelial cells), reduced expression of the protein VEGF in the lung, and increased blood pressure in the lung arteries. When rats with pulmonary fibrosis were treated with VEGF, they recovered normal lung artery pressure through reduced apoptosis of endothelial cells in the lung; however, their fibrosis worsened. This link between endothelial cell apoptosis in the setting of pulmonary fibrosis and the development of pulmonary hypertension may be crucial in generating novel therapeutics for treating this combination of conditions.

TITLE: VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats

AUTHOR CONTACT:
Martin Kolb
McMaster University, Hamilton, Ontario, Canada.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36136

Source:
Karen Honey
Journal of Clinical Investigation