Progressive Disruption of Sphingosine-1-Phosphate Receptor 1 Correlates with Blood-Brain Barrier Leakage in A Rat Model of Chronic Hypoxic Hypoperfusion.

Endothelial dysfunction and blood-brain barrier (BBB) leakage have been suggested as a fundamental role in the development of cerebral small vessel disease (SVD) pathology. However, the molecular and cellular mechanisms that link cerebral hypoxic hypoperfusion and BBB disruption remain elusive. Sphingosine-1-phosphate (S1P) regulates the BBB integrity by binding to its receptor isoform 1 (S1PR1) on endothelial cells. This study tested the hypothesis that hypoxic hypoperfusion triggers capillary endothelial S1PR1 disruption, which compromises BBB integrity and leads to SVD-related neuropathological changes, using a chronic hypoxic hypoperfusion model with BBB dysfunction. Spontaneously hypertensive rat stroke-prone underwent unilateral carotid artery occlusion (UCAO) followed by a Japanese permissive diet (JPD) for up to 9 weeks. Selective S1PR1 agonist SEW2871 was used to activate S1PR1. Significant progressive reduction of S1PR1 was detected in rat brains from 4 to 9 weeks following UCAO/JPD onset, which was also detected in cerebral vasculature in human SVD. S1PR1 activation by SEW2871 significantly reduced lesions in both white and grey matter and ameliorated cerebral blood flow. SEW2871 reversed the loss of endothelial S1PR1 and tight junction proteins, and significantly attenuated UCAO/JPD induced accumulation of neuronal phosphorylated tau. This protective role of SEW2871 is associated with promotion of Akt phosphorylation and inhibition of S1PR2/Erk1/2 activation. Our data suggest S1PR1 signalling as a potential molecular mechanistic basis that links hypoxic hypoperfusion with BBB damage in the neuropathological cascades in SVD. The reversal of BBB disruption through pharmacological intervention of S1PR1 signalling likely reveals a novel therapeutic target for SVD.

Nephrin is necessary for podocyte recovery following injury in an adult mature glomerulus.

Nephrin (Nphs1) is an adhesion protein that is expressed at the podocyte intercellular junction in the glomerulus. Nphs1 mutations in humans or deletion in animal genetic models results in a developmental failure of foot process formation. A number of studies have shown decrease in expression of nephrin in various proteinuric kidney diseases as well as in animal models of glomerular disease. Decrease in nephrin expression has been suggested to precede podocyte loss and linked to the progression of kidney disease. Whether the decrease in expression of nephrin is related to loss of podocytes or lead to podocyte detachment is unclear. To answer this central question we generated an inducible model of nephrin deletion (Nphs1Tam-Cre) in order to lower nephrin expression in healthy adult mice. Following tamoxifen-induction there was a 75% decrease in nephrin expression by 14 days. The Nphs1Tam-Cre mice had normal foot process ultrastructure and intact filtration barriers up to 4-6 weeks post-induction. Despite the loss of nephrin expression, the podocyte number and density remained unchanged during the initial period. Unexpectedly, nephrin expression, albeit at low levels persisted at the slit diaphragm up to 16-20 weeks post-tamoxifen induction. The mice became progressively proteinuric with glomerular hypertrophy and scarring reminiscent of focal and segmental glomerulosclerosis at 20 weeks. Four week-old Nphs1 knockout mice subjected to protamine sulfate model of podocyte injury demonstrated failure to recover from foot process effacement following heparin sulfate. Similarly, Nphs1 knockout mice failed to recover following nephrotoxic serum (NTS) with persistence of proteinuria and foot process effacement. Our results suggest that as in development, nephrin is necessary for maintenance of a healthy glomerular filter. In contrast to the developmental phenotype, lowering nephrin expression in a mature glomerulus resulted in a slowly progressive disease that histologically resembles FSGS a disease linked closely with podocyte depletion. Podocytes with low levels of nephrin expression are both susceptible and unable to recover following perturbation. Our results suggest that decreased nephrin expression independent of podocyte loss occurring as an early event in proteinuric kidney diseases might play a role in disease progression.

High-resolution chromoendoscopy for classifying colonic polyps: a multicenter study.

BACKGROUND: Chromoendoscopy may reliably separate adenomatous from nonadenomatous polyps. The aim of this multicenter trial was to determine the accuracy of high-resolution chromoendoscopy for the determination of colonic polyp histology. METHODS: This multicenter trial included 4 academic centers and a primary care practice. In 299 patients referred for routine colonoscopy or sigmoidoscopy, 520 polyps 10 mm in size were sprayed with indigo carmine dye. Using a high-resolution endoscope, the endoscopist predicted the histology of each polyp based on its surface characteristics. Hyperplastic polyps had a "pitted" surface pattern of orderly arranged "dots" that resembled surrounding normal mucosa. Adenomatous polyps had at least one surface "groove" or "sulcus." Each polyp was subsequently resected for histopathologic evaluation. RESULTS: The resected polyps were comprised by 193 adenomas (37%), 225 hyperplastic polyps (43%), and 102 "other" types (20%). Forty polyps (7.7%) could not be classified by high resolution chromoendoscopy with indigo carmine dye. For the remaining polyps, the sensitivity, specificity, and negative predictive value of indigo carmine dye staining for adenomatous polyps were, respectively, 82%, 82%, and 88%. The results were consistent among the academic centers and the primary care practice. CONCLUSIONS: High-resolution chromoendoscopy with indigo carmine dye demonstrates morphologic detail of diminutive colorectal polyps that can reliably be used to separate adenomatous from nonadenomatous polyps.