Tracking Acute Kidney Injury
Dr. Eisei Noiri and colleagues at the University of Tokyo, Japan identified a novel biomarker to monitor acute kidney injury. They present their data in the April 2009 issue of The American Journal of Pathology.
Acute kidney injury may be reversible if treated promptly and appropriately. Novel biomarkers therefore need to be developed to identify injury at early time points as well as to estimate the severity of the damage.
Negishi et al examined whether levels of urinary L-type fatty acid-binding protein (L-FABP), a protein found in the kidney that is secreted in the urine upon kidney injury, could be used to monitor acute kidney injury. Levels of L-FABP correlated with the level of acute kidney injury at significantly earlier time points than levels of conventional renal markers such as blood urea nitrogen (BUN) or urinary N-acetyl-D-glucosaminidase (NAG). In addition, L-FABP showed better correlation than BUN or NAG with final histological injury scores, especially at early time points.
L-FABP thus represents a better choice than conventional renal markers for evaluating early acute kidney injury. Future studies will “evaluat[e] various human AKI populations … to confirm the significance of urinary L-FABP as a forecasting biomarker of pathological and functional damage.”
Negishi K, Noiri E, Doi K, Maeda R, Sugaya T, Portilla D, Fujita T : Monitoring of urinary L-type fatty acid binding protein predicts histological severity of acute kidney injury. Am J Pathol 2009, 174: 1154-1159
New Target for Alzheimer’s Disease Therapy
Researchers at the VU University Medical Center, Amsterdam and the University of Amsterdam, The Netherlands discovered that the unfolded protein response contributes to nerve cell death in Alzheimer’s Disease. This report can be found in the April 2009 issue of The American Journal of Pathology.
Alzheimer’s disease is an incurable, degenerative, terminal form of dementia, thought to be caused in part by the presence of “tangles” of misfolded proteins. The unfolded protein response protects cells from the toxic effects of accumulated misfolded proteins; however, prolonged activation of the unfolded protein response, such as in Alzheimer’s disease, may lead to cell death.
Hoozemans et al hypothesized that the unfolded protein response contributed to neurodegeneration in Alzheimer’s disease partially though its effects on the accumulation of hyperphosphorylated tau, a major component of tangles in Alzheimer’s disease patients. They found that markers of the unfolded protein response were expressed in areas of tau accumulation in patients with Alzheimer’s disease. These unfolded protein response-related proteins were expressed early, in pre-tangle neurons, but were absent in tangle neurons.
This report suggests that “unfolded protein response activation occurs at an early stage of neurofibrillary degeneration and … that the prolonged activation of the [unfolded protein response] is involved in both tau phosphorylation and neurodegeration in [Alzheimer’s Disease] pathogenesis. … Future studies will address the therapeutic opportunities of this pathway for the treatment of [Alzheimer’s Disease] and other tauopathies.”
Hoozemans JJM, van Haastert ES, Nijholt DAT, Rozemuller AJM, Eikelenboom P, Scheper W: The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 2009, 174: 1241-1251
Bacterial Toxin Leads to Systemic Infection
A group led by Dr. Michael Klapproth at Emory University, Atlanta suggests that bacterial lymphotoxin disrupts intestinal epithelial barrier function. They report these findings in the April 2009 issue of The American Journal of Pathology.
Numerous bacterial species commonly live in the human gut. These bacteria contribute to digestion, but also may cause disease. Some bacteria, such as Escheria coli (E. coli) or Citrobacter rodentium (C. rodentium), can breach the intestinal epithelial barrier, entering the blood and causing systemic infection.
Lymphostatin, a toxin produced by gram negative bacteria including E. coli and C. rodentium, has been associated with bacterial virulence. To determine if lymphostatin affects epithelial barrier integrity, Babbin et al generated two strains of C. rodentium, CrGIM21 and CrPrM5, with different mutations in lymphostatin. Whereas wild-type C. rodentium disrupted epithelial barrier function, CrGIM21 and CrPrM5 had reduced effects on two aspects of epithelial cell function. These data suggest that lymphostatin may be a strong target candidate for treatment of enteric gram negative bacteria.
Dr. Klapporth and colleagues postulate that “therapeutic interventions in form of specific immunoglobulins directed against lymphostatin and its enzymatic activities might provide an attractive alternative to antibiotics in treating intestinal injury and preventing extraintestinal manifestations of Gram negative infection.”
Babbin BA, Sasaki M, Gerner-Schmidt KW, Nusrat A, Klapproth J-M A: The bacterial virulence factor lymphostatin compromises intestinal epithelial barrier function by modulating Rho GTPases. Am J Pathol 2009, 174: 1347-1357
Mouse Model of Human Psoriasis
Researchers led by Nicole Ward at Case Western Reserve University, Cleveland have developed a new mouse model to study human psoriasis. These findings are presented in the April 2009 issue of The American Journal of Pathology.
Psoriasis is a chronic inflammatory disease that causes red scaly patches to appear on the skin. It is characterized by excessive skin production, formation of new blood vessels, and the presence of white blood cells. Study of psoriasis has been limited, however, due to the absence of a mouse model that adequately reproduces these symptoms.
Over-expression Tie-2, a molecule involved in the formation of new blood vessels, in two types of skin cells, epithelial cells and keratinocytes, has provided the best psoriasis model to date. To determine whether Tie-2 over-expression in epithelial cells or keratinocytes resulted in the psoriasis phenotype, Wolfram et al engineered two new mouse models in which Tie-2 expression was limited to either epithelial cells or keratinocytes. Only the keratinocyte-restricted Tie-2 mice developed symptoms similar to human psoriasis. These symptoms were reduced by treatment with cyclosporin A, a common psoriasis therapy. Keratinocyte-restricted Tie-2 mice, therefore, may serve as an animal model for human psoriasis.
The psoriasis model developed by Dr. Ward’s group “bears a striking resemblance to human psoriasis, meeting multiple criteria at the clinical, histological, biochemical, immunophenotype, and pharmacologic levels … and therefore will become important for studying pathological mechanisms of psoriasis and pre-clinical testing of new therapeutics.”
Wolfram JA, Diaconu D, Hatala DA, Rastegar J, Knutsen DA, Lowther A, Askew D, Gilliam AC, McCormick TS, Ward NL: Keratinocyte but not endothelial cell specific over-expression of Tie-2 leads to the development of psoriasis. Am J Pathol 2009, 174: 1443-1458
New Marker for Prostate Cancer Progression
Avraham Raz and colleagues at the University of Michigan have identified a cleaved form of galectin-3 as a marker for prostate cancer progression. These data are presented in the April 2009 issue of The American Journal of Pathology.
Prostate cancer is a common malignancy among men over the age of 50. The stage at which prostate cancer is diagnosed is critical for determining prognosis as well as choosing appropriate therapies.
Decreased expression of the marker galectin-3 has been reported to correlate with neoplastic progression in prostate cancer; however, increased levels of galectin-3 have been linked to tumorigenicity in a number of other tumor types. In order to reconcile this difference, Wang et al hypothesized that galectin-3 was cleaved during prostate cancer progression. They identified cleaved galectin-3 in later stage prostate cancer, and determined that reducing levels of galectin-3 inhibited the development of metastatic prostate cancer. Thus, cleaved galectin-3 may serve as a diagnostic marker and therapeutic target for prostate cancer progression.
Dr. Raz’s group “show[s] that galectin-3 is cleaved during the progression of prostate cancer and might be associated with metastasis, cell growth, and tumorigenicity. … Expression of intact versus cleaved galectin-3 thus might be used as a marker for prognosis of prostate cancer and a therapeutic target for the treatment of prostate cancer.”
Wang Y, Nangia-Makker P, Tait L, Balan V, Hogan V, Jienta KJ, Raz A: Regulation of prostate cancer progression by galectin-3. Am J Pathol 2009, 174: 1515-1523