Transforming Growth Factor-βa (TGF-β1) Contributes to Kidney Disease
Dr. Wilhelm Kriz and colleagues at the University of Heidelberg, Heidelberg, Germany; the University of Paris, Paris, France; the University of Zurich, Zurich, Switzerland; the University of Berlin, Berlin, Germany; the University of Leipzig, Leipzig, Germany; and the Pennsylvania State University, University Park, Pennsylvania demonstrate that TGF-β1 contributes to kidney disease. Their report can be found in the August 2010 issue of the American Journal of Pathology.
Chronic kidney disease and end stage renal disease affect more than 2 out of every 1,000 people in the United States. Diabetes and high blood pressure are the two most common causes of chronic kidney disease.
Fibrosis in the kidney is one of the key causes of progressive renal failure. High levels of the inflammatory molecule TGF-β1 in the kidney tubules due to tissue damage can cause fibrosis as well as nephron degeneration, resulting in loss of kidney function. To clarify the mechanisms regulating TGF-β1-mediated renal fibrosis, Koesters et al expressed high levels of TGF-β1 in renal tubules of mice. Nephron degeneration in this system was mediated by decomposition of the tubular cells. These data suggest that TGF-β1 may play a novel role in cell death of renal cells, thus contributing to renal fibrosis.
Dr. Kriz’s group “uncover[ed] a novel potential role of TGF-β1, i.e. the induction of autophagy in renal epithelial cells. Its relevance under more usual pathological conditions as a possible further mechanism of programmed cell death remains to be established.”
Koesters R, Kaissling B, LeHir M, Picard N, Theilig F, Gebhardt R, Glick AB, Hähnel B, Hosser H, Gröne H-J, Kriz W: Tubular overexpression of transforming growth factor β 1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol 2010, 177:632-643
New Criteria for T-Cell Lymphoma Diagnosis
A group led by Dr. Mario Colombo of the Istituto Nazionale dei Tumori, Milan, Italy and Dr. Stefano Pileri of the Bologna University School of Medicine, Bologna, Italy has discovered new diagnostic criteria to differentiate peripheral T-cell lymphomas (PTCLs). They present these findings in the August 2010 issue of the American Journal of Pathology.
PTCLs comprise a group of rare and aggressive non-Hodgkin lymphomas that develop from T-cells in different stages of maturity. These diseases have a poor prognosis, with a 5-year survival rate of around 25%.
Subtype differentiation of peripheral T-cell lymphomas, such as autoimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphomas of non-specific origin (PTCL/NOS), is critical for the application of specific therapeutic strategies. Tripodo et al therefore examined the immunological microenvironment of PTCLs to find diagnostic criteria to differentiate AITLs and PTCL/NOS. They found that two types of immune cells, T helper 17 (Th17) cells and mast cells, directly contributed to the pro-inflammatory microenvironment of AITLs but not PTCL/NOS. From their data, they propose that AITL cells may directly recruit mast cells, which then secrete factors that result in the pro-inflammatory, Th17-generating microenvironment that leads to autoimmunity in these patients.
Tipodo and colleagues suggest “the immunological microenvironment of AITL, differently from that of PTCL/NOS, is characterized by the abundance of mast cells likely recruited by CXCL-13, produced, at least in part, by the neoplastic clone of Tfh derivation. In the AITL environment, infiltrating MCs might promote inflammation tipping the balance between immune regulation and autoimmunity and contributing to the local changes occurring in AITL-infiltrated tissues. The possible clinical relevance of microenviromental patterns as well as the potential therapeutic impact of strategies interfering in such dynamics surely warrant further investigation.”
Tripodo C, Gri G, Piccaluga PP, Frossi B, Guarnotta C, Piconese S, Franco G, Vetri V, Pucillo CE, Florena AM, Colombo MP, Pileri SA: Mast cells and Th17 cells contribute to the lymphoma-associated pro-inflammatory microenvironment of angioimmunoblastic T-cell lymphoma. Am J Pathol 2010 177: 792-802
Novel Cause for Genetic Tooth Decay
Researchers led by Dr. Catherine Chaussain of the University of Paris Descartes implicate a novel peptide in impaired dentin mineralization in rickets. They report their data in the August 2010 issue of the American Journal of Pathology.
Rickets, the softening of bones in children, is often caused by vitamin D deficiency due to severe malnutrition. Rickets is one of the most frequent childhood diseases in developing countries and is associated with severe bone deformities, including dental ailments due to impaired dentin mineralization.
Some cases of rickets, such as familial hypophosphatemic rickets, have a genetic basis. These cases are often caused by a mutation in the protein PHEX. Boukpessi et al hypothesized that PHEX impairment resulted in the release of a peptide, ASARM, which is known to inhibit dentin mineralization. They observed that ASARM was abnormally produced in patients with familial rickets, and that both symptoms and ASARM production could be attenuated by a diet high in vitamin D and phosphate during growth. The presence of the ASARM peptide may thus contribute to impaired dentin mineralization in rickets, in a manner compensated for by vitamin D and phosphate.
Dr. Chaussain and colleagues suggest that “the release of this peptide may partially explain the impaired dentin mineralization associated with the disease in teeth from hypophosphatemic patients with mutation of the PHEX gene. However, treatment during growth may limit the clinical consequences of this anomaly in the dentin of permanent teeth. This observation highlights the importance of improving phosphate and vitamin D environment on dentin mineralization, which compensates the adverse effect of PHEX mutation.”
Boukpessi T, Gaucher C, Léger T, Salmon B, Le Faouder J, Willig C, Rowe PS, Garabédian M, Meilhac O, Chaussain C: Abnormal presence of the MEPE-derived ASARM peptide in human hypophosphatemic dentin. Am J Pathol 2010, 177: 803-812
Preventing HIV-associated Nephropathy
Dr. Pravin C. Singal and colleagues at the Feinstein Institute for Medical Research, Manhasset, NY; the Texas Health Science Center, San Antonio, Texas; and New York Medical College, Valhalla, NY have identified mammalian target of rapamycin (mTOR) as a therapeutic target for HIV-associated nephropathy. These results are presented in the August 2010 issue of the American Journal of Pathology.
HIV-associated nephropathy, or kidney disease that develops in association with HIV infection, usually occurs only with advanced disease. HIV-associated nephropathy may be caused by direct HIV-1 infection in the renal cells, with resulting renal damage through the viral gene products, or by changes in the release of inflammatory molecules during HIV infection.
HIV-associated nephropathy is characterized by cell proliferation in affected kidney lesions. To determine if mTOR, which plays a key role in cell growth, was involved in this proliferative phenotype, Kumar et al examined mTOR activation in a mouse model of the disease. Both mTOR and its downstream targets were activated at higher levels in diseased mice as compared with controls, indicating enhanced activation of the mTOR signaling pathway. In addition, both mTOR activation and renal disease could be blocked by treatment with rapamycin, which inhibits the mTOR pathway. This report therefore supports mTOR as a therapeutic target for HIV-associated nephropathy.
Dr. Singal’s group concludes that “mTOR pathway activation is contributing to both the proliferative phenotype as well as to the development of [HIV-associated nephropathy.”
Kumar D, Konkimalla S, Yadav A, Sataranatarajan K, Kasinath BS, Chander PN, Singhal PC: HIV-associated Nephropathy: Role of mTOR Pathway: Am J Pathol 2010, 177: 813-821
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The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.