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This Month in AJP

    Open AccessPublished:August 27, 2014DOI:https://doi.org/10.1016/j.ajpath.2014.07.023

        The Role of Pericytes in Diabetic Retinopathy

        Both type 1 and type 2 diabetes patients are at risk of diabetic retinopathy, but the relative contribution of specific cellular components to the pathobiology of diabetic retinopathy remains undefined. Valdez et al (Am J Pathol 2014, 184:2618–2626) addressed this issue using an inducible model of pericyte loss in nondiabetic mice conditionally expressing a diphtheria toxin receptor in mural cells to examine the acute effects of pericyte loss on adult retinal microvasculature. Five days after administering diphtheria toxin in these adult mice, retinal vasculature exhibited changes similar to those observed in diabetic patients, including microaneurysms and increased vascular permeability. These results suggest that pericyte cell loss is sufficient to trigger retinal microvascular degeneration and that pericyte protection, rescue, or replacement may be a viable therapeutic target.

        Three-Probe Test Detects Prostate Cancer Progression

        Sensitive and specific tests to distinguish indolent versus aggressive prostate cancers are lacking. Heselmeyer-Haddad et al (Am J Pathol 2014, 184:2671–2686) assessed previously identified genetic markers to understand genomic alteration dynamics in patients with or without progression after radical prostatectomy. No differences were observed in the percentage of cells with prostate cancer-specific TMPRSS2-ERG fusion between samples with or without progression. Tumors from patients who progressed had more chromosomal gains and losses and showed a higher degree of selection for a predominant clonal pattern. PTEN loss was the most frequent aberration in progressors, followed by TBL1XR1 gain. MYC gain was observed in one progressor tumor, which was the only lesion with an ERG gain but no TMPRSS2-ERG fusion. Thus, a probe set consisting of PTEN, MYC, and TBL1XR1 may detect progressors with high specificity and sensitivity in a routine pathology setting.

        Tsp1 Deficiency Delays Renal Failure Onset

        Thombospondin-1 (Tsp1), a multifunctional matricellular protein, promotes chronic kidney disease progression. To explore the mechanisms of Tsp1 action, Zeisberg et al (Am J Pathol 2014, 184:2687–2698) compared chronic kidney disease progression in Col4A3 knockout mice with that of Col4A3;Tsp1 double-knockout mice. Tsp1 absence significantly delayed the decline of excretory kidney function. Disease progression was predominantly associated with fibrosis and inflammation in Col4A3 knockout and Col4A3;Tsp1 double-knockout mice, respectively. Altered disease progression was due to impaired activation of latent transforming growth factor-β1 activation in the absence of Tsp1 in vivo and in vitro. Therapeutic strategies should target both fibrosis and inflammation as they are independent entities, each contributing to expansion of the interstitium and decline of renal function.

        Cathepsin E Promotes Pulmonary Emphysema

        The molecular mechanisms of emphysema, a major subset of chronic obstructive pulmonary disease, remain poorly defined. Because cathepsins have been implicated in mediating alveolar destruction, Zhang et al (Am J Pathol 2014, 184:2730–2741) examined their role in lung disease. Human chronic obstructive pulmonary disease lung tissues had markedly increased cathepsin E in the epithelium. Transgenic mice overexpressing cathepsin E in epithelia exhibited increased levels of E3 ubiquitin ligase parkin and mitochondrial fission protein dynamin-related protein 1 in addition to caspase activation/apoptosis and ultimately loss of lung parenchyma resembling emphysema. In vitro or in vivo inhibition of dynamin-related protein 1 with a small molecule inhibitor prevented cathepsin E –induced apoptosis and emphysema. These findings highlight a novel role of cathepsin E and mitochondrial fission in the pathogenesis of chronic obstructive pulmonary disease.

        Hypertension Alters Calcium Homeostasis in Skeletal Muscle

        The mechanisms underlying the development of hypertension-associated skeletal muscle pathology are poorly defined. Liantonio et al (Am J Pathol 2014, 184:2803–2815) assessed whether calcium homeostasis, a biomarker of muscle function, is altered in the muscles of spontaneously hypertensive rats. Hypertension caused a phenotype-dependent dysregulation of calcium homeostasis; the resting intracellular calcium of leg muscles of spontaneously hypertensive rats was differently altered with respect to the related muscles of normotensive Wistar-Kyoto rats. Soleus muscles of spontaneously hypertensive rats showed reduced activity of the sarcoplasmic reticulum and decreased sarcolemmal calcium permeability at rest and after store-operated calcium entry activation. The expression levels of some store-operated calcium entry components, excitability, and resting chloride conductance were also altered. These findings identify druggable targets for the treatment of muscle weakness affecting hypertensive patients.

        Linked Article

        • Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission
          The American Journal of PathologyVol. 184Issue 10
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            Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing.
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        • Retinal Microangiopathy in a Mouse Model of Inducible Mural Cell Loss
          The American Journal of PathologyVol. 184Issue 10
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            Diabetes can lead to vision loss because of progressive degeneration of the neurovascular unit in the retina, a condition known as diabetic retinopathy. In its early stages, the pathology is characterized by microangiopathies, including microaneurysms, microhemorrhages, and nerve layer infarcts known as cotton-wool spots. Analyses of postmortem human retinal tissue and retinas from animal models indicate that degeneration of the pericytes, which constitute the outer layer of capillaries, is an early event in diabetic retinopathy; however, the relative contribution of specific cellular components to the pathobiology of diabetic retinopathy remains to be defined.
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        • Thrombospondin-1 Deficiency Causes a Shift from Fibroproliferative to Inflammatory Kidney Disease and Delays Onset of Renal Failure
          The American Journal of PathologyVol. 184Issue 10
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            Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level–matched Col4a3 KO mice.
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        • Calcium Homeostasis Is Altered in Skeletal Muscle of Spontaneously Hypertensive Rats: Cytofluorimetric and Gene Expression Analysis
          The American Journal of PathologyVol. 184Issue 10
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            Hypertension is often associated with skeletal muscle pathological conditions related to function and metabolism. The mechanisms underlying the development of these pathological conditions remain undefined. Because calcium homeostasis is a biomarker of muscle function, we assessed whether it is altered in hypertensive muscles. We measured resting intracellular calcium and store-operated calcium entry (SOCE) in fast- and slow-twitch muscle fibers from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) by cytofluorimetric technique and determined the expression of SOCE gene machinery by real-time PCR.
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        • Single-Cell Genetic Analysis Reveals Insights into Clonal Development of Prostate Cancers and Indicates Loss of PTEN as a Marker of Poor Prognosis
          The American Journal of PathologyVol. 184Issue 10
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            Gauging the risk of developing progressive disease is a major challenge in prostate cancer patient management. We used genetic markers to understand genomic alteration dynamics during disease progression. By using a novel, advanced, multicolor fluorescence in situ hybridization approach, we enumerated copy numbers of six genes previously identified by array comparative genomic hybridization to be involved in aggressive prostate cancer [TBL1XR1, CTTNBP2, MYC (alias c-myc), PTEN, MEN1, and PDGFB] in six nonrecurrent and seven recurrent radical prostatectomy cases.
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